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Latest revision as of 21:37, 8 October 2019

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]

Overview

Surface epithelium of ovaries (OSE), once mistakenly referred as germinal epithelium, consists of single layer of flat to cuboidal epithelial cells. It is characterized by keratin types found in simple epithelium and functions in exchange between peritoneal cavity and the ovaries in addition to ovarian cycle. During embryonic development, surface epithelium of ovaries is a part of celomic epithelium. The future surface epithelium of ovaries then forms part of gonadal blastema and then undergoes a transformation cycle, multilayered papillary epithelium develops from simple flat to cuboidal epithelium but reverts back to simple flat to cuboidal epithelium by term. The most important functions of human surface epithelium of ovaries are its role in transport and exchange between peritoneal cavity and ovaries, and its function in repair and rupture during ovulation. Ovarian surface epithelium undergo epithelio-mesenchymal transformation to replace ovarian stroma in ovulatory repair. The previous proposition regarding the origin of epithelial ovarian cancers was that these tumors originated from surface epithelium of the ovaries and the neoplastic and metaplastic changes led to their differentiation into various histological subtypes such as serous tumors, clear cell carcinoma and endometrioid tumors. But apparent consistencies in this theory has led to development of alternate theories such as origin of neoplastic cells from fallopian tubes and endometrium.

Pathophysiology

Embryogenesis

Celomic epithelium → Peritoneal mesothelium surrounding the ovary → Metaplasia to ovarian surface epithelium^[1]^[2]

During embryonic development, surface epithelium of ovaries is a part of celomic epithelium.^[2]
Celomic epithelium itself is derived from mesothelium and forms lining of intraembryonic celom.^[2]
The future surface epithelium of ovaries then forms part of gonadal blastema and then undergoes a transformation cycle, multilayered papillary epithelium develops from simple flat to cuboidal epithelium but reverts back to simple flat to cuboidal epithelium by term.^[2]
It is important to note that ovarian surface epithelium is the part of celomic epithelium that overlies the presumptive gonads and the celomic epithelium in proximity of gonads also gives rise to Mullerian (paramesonephric) ducts, that in future will develop into epthelium of most of the female reproductive tract including oviducts, endometrium and a part of cervix.^[2]^[3]
Ovarian surface epithelium has also been postulated to give rise or form a part of ovarian granulosa cells during embryonic development.^[2]^[3]

Structural Characteristics of Ovarian Surface Epithelium in Adults


Cell type	Surface expression	Intercellular connection	Basement membrane
Single layer squamous-to-cuboidal epithelium	Keratin Mucin antigen MUC1 17β-hydroxysteroid dehydrogenase Cilia	Simple desmosomes Incomplete tight junctions Integrins Cadherins	Loosely attached Tunica albuginea that is less conspicuous of its testicular counterpart

Keratin types that are expressed by ovarian surface epithelium are characteristic of simple epithelia such as keratin type 7, 8, 18 and 19.^[2]^[4]
Catherins expressed by surface epithelium of ovaries may indicate potential for neoplastic transformation as summarized:^[2]^[4]^[5]^[6]^[7]
- Surface epithelium of ovaries typically express N-cadherin.
- E-cadherin is typically expressed in regions where cells are columnar.
- This selective expression of E-cadherin in regions of metaplastic epithelium may indicate propensity for neoplastic transformation.
- P-catherin, normally absent in adult surface epithelium of ovaries, is expressed in adenocarcinoma of ovaries.

Functions

Two most important functions of human surface epithelium of ovaries are its role in transport and exchange between peritoneal cavity and ovaries, and its function in repair and rupture during ovulation.^[2]^[5]^[8]
At present, its role in ovulatory rupture is not well-understood and is controversial. It is hypothesized that it contributes to follicular rupture through production of proteolytic enzymes.^[2]^[5]
Epithelial need and ability of proliferation for repair of rupture and ovulatory defects is well-established and is thought to contribute the most in carcinogenesis of ovarian epithelium tumors.^[2]
Ovarian surface epithelium undergo epithelio-mesenchymal transformation to replace ovarian stroma in ovulatory repair.^[2]
The differentiation of surface epithelium of ovaries is, however, different from other epithelia because of its ability of differentiate into ectopic epithelium such as that of epithelium formed by Mullerian ducts.^[2]

Role of Hormones and Growth Factors on Surface Epithelium


Gonadotropin-releasing hormone and gonadotropins^[2] ^[9]	Cell proliferation
Epidermal growth factor (EGF)^[2] ^[4]^[10]^[11]	Cell proliferation and differentiation Increased survival
Steroids^[2] ^[12]^[13]	Decreased expression of GnRH receptors (estrogen) Regulation of hepatocyte growth factor and epidermal growth factor 9estrogen) Decreased expression of Transfroming growth factor β receptors (5α-dihydrotestosterone) May have direct effect on proliferation stimulation
Fibroblast growth factor (FGF)^[2] ^[14]	Cell proliferation Increased survival
Platelet-derived growth factor (PDGF)^[2] ^[15]	Cell proliferation
Tissue necrosis factor-α (TNF-α)^[2] ^[16]^[17]	Cell proliferation Increased TNFα expression
Transfroming growth factor β (TGF-β)^[2] ^[18]	Decreased growth
Hepatocyte growth factor (HGF)^[2] ^[19]^[20]	Decreased cellular adhesion Increased survival and growth
Cytokines^[2] ^[21]^[22]	Regulation of immune response May increase vasculogenesis and survival

The Origin of Neoplasia in Epithelial Ovarian Cancer: A Mystery to Solve

The previous proposition regarding the origin of epithelial ovarian cancers was that these tumors originated from surface epithelium of the ovaries and the neoplastic and metaplastic changes led to their differentiation into various histological subtypes such as serous tumors, clear cell carcinoma and endometrioid tumors.^[23]^[24]^[25]^[26]^[27]
However the surface epithelium of ovaries is derived from mesothelium and ovarian carcinoma resembled more closely to tissues derived from Mullerian ducts rather than ovarian mesothelium derived surface epithelium. For example serous cancer histology resembles fallopian tube epithelium and that of transitional cells tumor resembles urinary bladder. Likewise endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis, and Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives.^[23]^[24]^[25]^[26]^[27]^[28]
Secondly the genetic profile also overcasts shadows of doubt about origin of these neoplasms from ovarian surface epithelium. The presence of identical TP53 mutations in serous tubal intra-epithelial tumors and ovarian serous tumors puts a question mark on ovarian origin theory. Gene expression profiling also demonstrated the presence of similarities between serous tubal intra-epithelial tumors and ovarian serous tumors. The various theories of origin of epithelial ovarian cancers have been discussed below.^[25]^[26]^[27]^[29]^[30]

Ovarian Origin of Ovarian Epithelial Tumors

This simple theory states that ovarian epithelial tumors simply originate from surface epithelium of ovaries through various neoplastic changes. But recent data has highlighted the numerous inconsistencies in the theory that was once highly regarded as accurate.^[25]^[26]^[27]
Firstly surface epithelium of ovaries is derived from mesothelium and ovarian carcinoma resembled more closely to tissues derived from Mullerian ducts rather than ovarian mesothelium derived surface epithelium. For example serous cancer histology resembles fallopian tube epithelium and that of transitional cells tumor resembles urinary bladder. Likewise endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis, and Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives.^[23]^[24]^[25]^[26]^[27]^[28]
Secondly the presence of identical TP53 mutations in serous tubal intra-epithelial tumors and ovarian serous tumors puts a question mark on ovarian origin theory. Gene expression profiling also demonstrated the presence of similarities between serous tubal intra-epithelial tumors and ovarian serous tumors.^[25]^[26]^[27]^[29]^[30]
The expression of PAX8 and absence of calretinin in high grade serous tumors presents another problem with theory of ovarian origin because PAX8 is a Müllerian marker and calretinin is a mesothelium marker.^[26]^[27]
In 2001, a Dutch study revealed the presence of high grade serous carcinomas in fallopian tubes of women with genetic susceptibility to hereditary ovarian cancers with no evidence of such lesions in ovaries of same women. These lesions were termed as serous tubal intra-epithelial tumors.^[25]^[26]^[27]^[31]^[29]^[32]
Additional studies demonstrated the presence of similar lesions in fallopian tubes of women without genetic susceptibility to ovarian cancer. In cases when fallopian tubes were removed carefully along with ovarian and/or peritoneal serous cancer, the involvement of mucosa of the tubes were found to be involved in about 70% of the cases.^[25]^[26]^[27]^[31]^[29]^[32]
In an attempt to explain these apparent discrepancies it was postulated that invagination of ovarian epithelium into ovarian stroma creates “cortical inclusion cysts”. These cysts then undergo various metaplastic changes (coelomic metaplasia hypothesis) due to hormonal influence and repair mechanisms to give rise to ovarian epithelial cancer. Although these cysts are present but no such neoplastic and metaplastic transformation has been reported or observed until now. Additionally the observed cysts could dimply be the transplants from the fallopian tubes.^[25]^[26]^[27]^[33]
Another proposed theory is the implantation of tubal epithelium from fimbria into ovarian inclusion cysts due to their close contact during the ovulation process. This may explain the origin of serous tumor of the ovaries but unable to explain other tumor sub-types.^[25]^[26]^[27]

Secondary Müllerian System

This theory tries to explain this apparent enigma of existence of Müllerian epithelial lesions in locations not derived from Müllerian ducts such as ovaries and peritoneal cavity. Secondary Müllerian system consists of müllerian-type tissue lined cysts that are located in close proximity to the ovaries.^[34]^[25]^[26]^[27]
According to this hypothesis Müllerian tissues, considered by some as vestigial, are found in locations such as para-tubal and para-ovarian locations and these tissues or cysts, not the ovarian epithelium itself, give rise to epithelial ovarian neoplasms. These tumors, arising outside ovaries, then enlarge and become implants/or compress ovaries and present as ovarian tumors.^[23]^[25]^[26]^[27]
But there are number of problems this theory fails to explain. For example mucinous epithelial tumors of ovaries resemble intestinal epithelium rather than endocervical epithelium. Also transitional cell tumor resemble morphologically to bladder epithelium that is not a derivative of Müllerian system.^[25]^[26]^[27]^[28]
Another apparent flaw is that transition of these cysts lined by Müllerian-type epithelium, although present, to carcinoma has been very rare.^[25]^[26]^[27]

The Origin of Epithelial Ovarian Tumors from Fallopian Tubes and Endometrium

The evidence from recent studies indicate that majority of epithelial ovarian cancers have their origin outside ovaries, especially from fallopian tubes and endometrium. This idea is supported by several observations in a number of studies.^[25]^[26]^[27]
The histology of serous, endometrioid and clear cell carcinoma demonstrates that their morphology is similar to that fallopian tubes, and endometrium rather than ovarian epithelium.^[25]^[26]^[27]^[35]^[36]
Presence of PAX8, a Müllerian marker, and absence of calretinin, a mestothelial marker, further supports the theory. Moreover the genetic profile expression similarities and presence of similar TP53 mutation signatures in serous tubal intra-epithelial tumors and epithelial ovarian cancers also supports the extra-ovarian origin of epithelial ovarian cancer.^[25]^[26]^[27]^[29]^[30].
In 2001, a Dutch study revealed the presence of high grade serous carcinomas in fallopian tubes of women with genetic susceptibility to hereditary ovarian cancers with no evidence of such lesions in ovaries of same women. These lesions were termed as serous tubal intra-epithelial tumors.^[25]^[26]^[27]^[29]^[32]^[31]
Additional studies demonstrated the presence of similar lesions in fallopian tubes of women without genetic susceptibility to ovarian cancer. In cases when fallopian tubes were removed carefully along with ovarian and/or peritoneal serous cancer, the involvement of mucosa of the tubes were found to be involved in about 70% of the cases.^[25]^[26]^[27]^[29]^[32]^[31]
These tubal serous lesions were located in fimbria in almost all of the cases, giving rise to the proposition that serous tumors originated in fallopian tubes and then implantation into ovaries.^[25]^[26]^[27]^[37]^[29]^[38]
The association between adnexal malignant mixed mesodermal tumors and serous tubal intraepithelial tumors pints further in direction of tubal origin of these epithelial ovarian tumors.^[25]^[26]^[27]^[39]^[40]
Similarly morphologic and molecular studies have indicated that endometrioid and clear cell carcinoma of the ovaries have their origin in endometriosis. These studies suggest that these tumors arise from endometriomas, the endometriotic cysts that are present outside the normal endometrium.^[25]^[26]^[27]^[35]^[36]
This theory regarding the origin of endometrioid and clear cell carcinoma of the ovary is supported by the fact that tubal ligation that prevents endometriotic implants into ovary and peritoneum in endometriosis has a protective effect on endometrioid and clear cell type cancers but not on the serous cancer of the ovary because it doesn't occlude the connection between fimbria and the ovaries.^[25]^[26]^[27]^[41]^[42]

The Origin of Mucinous Tumors of Gastrointestinal Type and Transitional Cell (Brenner) Tumors: Still a Mystery to Solve

Mucinous and the transitional tumors of ovaries are two of the least common types of the epithelial ovarian tumors. In fact, most of the mucinous tumors in ovaries are secondary and primary tumors only form about 3% of all epithelial ovarian cancers. Mucinous epithelium in mucinous tumors of ovaries resemble more to intestinal mucinous epithelium rather than that of endocervix as was previously argued. Transitional cell tumors, on the other hand, are closer to bladder epithelium in histological studies.^[27]^[25]^[26]^[28]^[43]^[44]
Another study demonstrated the presence of Brenner tumor foci in mucinous cystadenoma in almost one fifth of the cases. Alternatively the association of mucinous tumors with Walthard cell nests, which are composed of transitional-type epithelium, also indicates the connection between mucinous and transitional tumors.^[27]^[25]^[26]^[43]^[44]

Pathogenesis

Secondary Müllerian System

Although ovarian surface epithelium is not a derivative of Müllerian ducts but ovarian epithelial cancers are characterized by presence of Müllerian lesions.^[34]
Serous carcinoma of ovary is though to originate from fallopian tubes while clear cell, endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis. Similarly Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives..^[23]^[24]
Secondary Müllerian system is a hypothesis that tries to explain this apparent enigma of existence of Müllerian epithelial lesions in locations not derived from Müllerian ducts such as ovaries and peritoneal cavity.^[46]^[24]
According to this hypothesis, Müllerian tissues, considered as vestigial, are found in locations such as para-tubal and para-ovarian locations and these tissues or cysts, not the ovarian epithelium itself, give rise to epithelial ovarian neoplasms.^[23]^[24]

Hereditary Ovarian Carcinoma: An Understanding of Genome

More than one fifth cases of ovarian epithelial cancers are found to have hereditary causes. These hereditary diseases/syndromes appear to possess heterogeneous, both in genetic anomalies and in clinical manifestations.^[47]^[48]
Majority of these hereditary cancers are caused by two genetic anomalies: a defect in so-called mismatch repair genes named as MLH1, MSH2, MSH6 and PMS2, and in DNA defects repair genes named as BRCA1 and BRCA2.^[47]^[48]^[45]^[49]

The Role of BRCA1 Gene in DNA Repair

BRCA1 is a protein that, through a complex interaction with other proteins such as tumor suppressors, regulators of cell cycle and other DNA repair genes, is involved in DNA repair pathways.^[47]^[48] ^[50]
This protein has two domains: amino-terminal RING domain and a BRCT domain. The former posses E3 ubiquitin ligase activity and the later facilitates phospho-protein binding.^[50]
Tumor suppressor role of both domains is highlighted by the fact that mutations in both domains have been found in breast and gynecological malignancies.^[50]
The major role of BRCA1 appears to sense and repair double stranded DNA breaks in homologous recombination.^[50]

Binding of BRCA1 to double stranded DNA breaks through its association with the abraxas–RAP80 macro-complex → processing of double stranded DNA breaks through interaction of BRCA1 with CtIP (transcription factor) and the MRN complex → The BRCA1–CtIP complex → CtIP-mediated 5′-end resection of double stranded DNA breaks

Another role of BRCA1 in Non-homologous end joining (NHEJ) pathway has also been proposed. Though still controversial, it has been suggested that BRCA1 plays a critical function by removal of Non-homologous end joining proteins such as p53-binding protein 1 (53BP1) from double stranded DNA breaks.^[50]
G1/S, S-phase and G2/M checkpoints activation during cell cycle has also been found defective in cells lacking or having mutated BRCA1. A brief interaction of BRCA1 with cell cycle is given below:^[50]

Phosphorylation of BRCA1 by ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related protein (ATR) → phosphorylation of p53 → transcriptional induction of the cyclin dependent kinase (CDK) inhibitor p21.

^[51]**A summary of BRCA1 activity and function in DNA damage repair**

The Role of BRCA2 Gene in DNA Repair

BRCA2, as opposed to BRCA1 that functions in multiple pathways involving DNA repair, has its primary role in homologous recombination (HR).^[47]^[48]^[50]
DNA-binding domain (DBD) of BRCA2 binds single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) and eight BRC repeats. The eight BRC repeats bind RAD51 (a recombinase).^[50]^[52]
The binding of BRCA2 to RAD51 leads to recruitment of RAD51 to double stranded DNA breaks, an essential step in homologous recombination double stranded DNA repair.^[50]^[52]^[53]
After recruitment, BRCA2 helps RAD51 in displacement of replication protein A (RPA) in single stranded DNA. It then prevents nucleation of RAD51 at double stranded DNA and promotes RAD51 filament formation on single stranded DNA.^[50]^[53]

The Connection Between BRCA1 and BRCA2

The common pathway that seems to link both BRCA! and BRCA2 proteins is homologous recombination mediated repair.^[50]^[54]^[55]
Partner and localizer of BRCA2 (PALB2) physically connects BRCA1 and BRCA2 through N-terminal coiled-coil domain and the C terminus.^[50]^[54]^[55]
The interaction between BRCA2 and PALB2 is observed for two critical function in homologous recombination mediated repair: interaction of RAD51 with replication protein A (RPA) in single stranded DNA and recruitment of BRCA2 and RAD51 on the site of DNA damage.^[50]

The Role of Mismatch Repair Genes

Mismatch repair genes mutated in pathogenesis of hereditary epithelial ovarian cancer include human MutS homolog (MSH2 and 6), the human MutL homolog (MLH1 and 3), and post-meiotic segregation MutL homolog (PMS2) genes.^[47]^[48]^[45]^[49]
A simplified version of repair mechanism by mismatch repair genes products is described below:^[49]^[56]

MutS homologs (MSHs) recognize the DNA mismatch → MutS homologs (MSHs) recruit MutL homologs (MLHs) → excision of mismatched DNA → DNA polymerase re-synthesizes DNA.

Cells deficient in mismatch repair mechanism develop high rate of mutations including DNA sequences that include microsatellite repeats, resulting in microsatellite instability. This microsatellite instability has been implicated in impaired or defective signaling transduction, DNA repair and apoptosis, transcriptional regulation and protein translocation, and immune regulation.^[45]^[49]^[56]

Mismatch repair genes and oncogenesis. Source: Courtesy of G. Multoff and J. Radons, Frontiers in oncology

TP53 Mutations and Loss of Tumor Suppression

TP53 is a tumor suppressor gene that encodes for a transcription factor. The transcription factor encoded by TP53, known as p53, is a major regulator of cell cycle.^[57]^[58]
Called by some as “Guardian of the Genome”, it is involved in variety of cellular functions such as cellular proliferation and cell cycle, apoptosis, and stability & integrity of the genome.^[59]^[58]

Template:Epithelial ovarian cancer

An Insight Into The Molecular Pathogenesis of Epithelial Ovarian Cancer

**Genetic alterations in cell cycle genes in epithelial ovarian cancer types.^[61]**

Dualistic Model

This model attempts to explain clinicopathological and molecular genetic features of epithelial tumors by diving them in two subgroups: type I and type II epithelial ovarian tumors.^[25]^[62]
Another advantage of this classification is that it tries to group precursor lesions with their putative malignant lesions.^[25]^[62]
Type I tumors generally arise from endometriosis or fallopian tubal related serous epithelium. They are clinically stable, exhibit less aggressive clinical course and a different genetic than that of Type II.^[63]^[64]
Type II tumors generally arise from fallopian tubal epithelium. They exhibit more aggressive clinical course and a different genetic profile relative to Type I.^[63]^[64]
Type I tumors are generally characterized by chromosomal stability and somatic mutations that may include KRAS, BRAF, PTEN, PIK3CA, CTNNB1, ARID1A and PPP2R1A. BRCA1 mutation, on the other hand, has not been observed and TP53 mutation is very rare.^[25]^[62]^[65]
Type II tumors are characterized by chromosomal instability. The mutations characteristic of high grade tumors, especially TP53 are common. TP53 has been reported in more than 90% of these tumors and a high proportion contains either BRCA mutations or BRCA related mutations such as RAD51, PALB2.^[25]^[66]^[67]
A simplified version of this classification is provided below:


Epithelial Ovarian Cancer
Type I	Type II
Low-grade serous carcinoma Endometrioid carcinoma Clear cell carcinoma Mucinous carcinoma Malignant Brenner tumor Seromucinous carcinoma	High-grade serous carcinoma Undifferentiated carcinoma Carcinosarcoma

Dualistic Model for Serous Tumor

Serous tumor provides, perhaps the most, evidence for the proposed model. Studies suggest that it exhibits distinct morphological and genetic types/stages that may explain the progression from benign tumor (cystadenoma) to low grade serous tumor.^[25]^[62]
This idea is supported by advances in discovery and understanding of so-called borderline serous tumors. These advances demonstrated that one type of these borderline tumors resembled benign serous tumors in their cinicopathological behavior and were named as “atypical proliferative serous tumor (APST)”. The other type behaved in way closer to low grade serous cancer and were termed as “micropapillary serous carcinoma (MPSC)”.^[25]^[62]^[68]
The absence of KRAS and BRAF mutation in serous cystadenoma but presence of these mutations in atypical proliferative serous tumor indicates that these mutations occur somewhat early in transformation of serous cystadenoma into atypical proliferative serous tumor.^[25]^[69]
More support was provided by studies that showed that genes involved in MAPK pathway were expressed more in micropapillary serous carcinoma than in atypical proliferative serous tumor. In addition, micropapillary serous carcinoma exhibited more chromosomal instability than atypical proliferative serous tumor.^[25]^[68]
This indicates the step-wise development of low grade serous carcinoma from benign cystadenoma with developemnet of abnormalities in KRAS, BRAF and MAPK pathways. A simplistic version is given below:^[25]^[70]^[71]^[72]

ERRB2 (mutation) → PI3K → AKT → mTOR → Cyclin D1 → cell cycle control and cellular survival → Tumor initiation and progression

↓

KRAS → BRAF → MEK → ERK → Cell cycle control and cellular survival → Tumor initiation and progression

PI3K (mutation) → AKT → Tumor initiation and progression

KRAS (mutation) → BRAF → MEK → ERK → Tumor initiation and progression

PI3K (mutation) → Tumor initiation and progression

BRAF (mutation) → MEK → ERK → Cell cycle control and cellular survival → Tumor initiation and progression

*ERK can directly promote tumor initiation, and cellular growth and survival or can promote these through activation of glucose transporter-1 and cyclin D1.^[25]

High grade serous carcinoma, on the other hand, is characterized by mutations rarely found in either of low grade serous carcinoma, micropapillary serous carcinoma and atypical prolferative serous tumor. Of these mutations, TP53 is the most common mutation and is found in >90% of the cases.^[25]^[67]
While BRCA1 and BRCA2 mutations occur in majority of familial high grade serous carcinoma, inactivation of BRCA1 and/or BRCA2 by indirect mechanisms such as mutation and/or inactivation of promoter occur more frequently in sporadic high grade serous cancer and have been observed in about half of these cancers.^[25]^[73]
The most noteworthy feature in molecular pathogenesis of high grade serous carcinoma is high level of DNA copy number gains or losses. These gains or losses are diffuse and include foci such as CCNE1 (cyclin E1), NOTCH3, AKT2, RSF1, and PIK3CA.^[25]^[74]

Pathogenesis of high grade serous carcinoma^[75] Normal fallopian tube epithelium comprises of both secretory and ciliated cells and stains negative for p53. The benign ‘p53 signature’: secretory cells that possess strong p53 expression and evidence of DNA damage but are not proliferative. When they progress to serous tubal intraepithelial carcinoma or ‘STIC’, they acquire nuclear pleomorphism, mitoses, and loss of polarity. Serous tubal intraepithelial carcinoma shares all these properties with invasive high grade serous epithelial ovarian cancer and clinical symptoms typically emerge with advanced disease.^[75]^[76]

Genetic Alterations in Clear Cell

Inactivating mutation of ARID1A. ARID1A encodes for a product that functions in tumor suppression and is observed in half of clear cell cancers.^[25]^[65]^[77]
Activating mutation of PIK3CA, also observed in about half of these tumors, results in actiavtion of PI3k pathway.^[25]^[78]
Deletion of PTEN, observed in about 20% of the cases, results in loss of tumor suppressor gene.^[25]^[79]
These alterations indicate the importance of PI3K/PTEN pathway in development of clear cell carcinoma of ovary.^[25]^[79]

**ARIDA loss and PIK3CA activation in clear cell cancer of ovaries.**^[80](A) ARID1A and PIK3CA alterations plot against TCGA datasets. Significance of association between ARID1A and PIK3CA mutations were determined using Fisher’s exact test. (B) Determination of CRE-deleted (*Arid1aΔ*) allele in samples of tumor DNA. (C) RT-PCR was used to detect ARID1A loss or *(Gt)Rosa26Pik3ca^*H1047R* transcripts. (D and E) Expression of ARID1A in normal ovaries (E) Expression of ARID1A in the normal ovarian surface epithelium (arrowhead). (F) ARID1A expression is not observed in the tumors. (H, I) Highest expression of P-AKT S473 in surface epithelium of ovaries in normal ovaries (E, arrowhead) and are greatly increased in ovarian tumors (F, arrowhead). Asterisk in E denotes an oocyte. (J,K) Morbid *Arid1a^fl/fl;(Gt)Rosa26Pik3ca^*H1047R* mouse at sacrifice with hemorrhagic ascites (inset), primary ovarian tumor of moderate size, and bilateral tumor metastases (arrowheads). (L,M) Morbid *Arid1a^fl/fl;(Gt)Rosa26Pik3ca^*H1047R* mouse at sacrifice with hemorrhagic ascites (inset), large primary ovarian tumor, and no visible metastases. The mice shown in *J-M* were sacrificed at 7 and 9 weeks post-AdCRE, respectively, because of visible ascitic fluid burden. (N,O) *Arid1a^fl/+;(Gt)Rosa26Pik3ca^*H1047R* mice at 11-weeks post-AdCRE showing no evidence for tumor formation. In K and M, dashed circles indicate primary ovarian tumor on injected ovary. In N, arrows denote the AdCRE injected ovary. In K, M, and O, asterisks denote the uninjected, control ovary.

Genetic Alterations in Endometrioid Tumors

Low grade endometrioid cancer also exhibits dysregulated either PI3K/PTEN pathway or Wnt/b-catenin signaling pathway. Later has been observed in about 40% of the low grade endometrioid tumors.^[25]^[81]^[82]^[83]
PI3K/PTEN pathway is deregulated either by activating mutations in PIK3CA or inactivation/deletion of PTEN, a tumor suppressor gene. Activating mutations of CTNNB1, that encodes β-catenin, are usually the cause for deregulated Wnt/b-catenin signaling pathway.^[25]^[81]^[82]^[83]
High grade endometrioid carcinoma, on the other hand, dooes not exhibit dysregulated PI3K/PTEN pathway or Wnt/b-catenin signaling pathway but frequently has TP53 mutations present.^[25]^[83]

Genetic Alterations in Mucinous Tumors

KRAS mutations are present in up to two thirds of these tumors and have also been used as molecular marker.^[25]^[84]^[85]


Possible genetic alteration in epithelial ovarian cancers
Protein	Normal function	Function in malignancy
Human Epidermal growth factor receptor (HER-1)^[86]^[87]	Promotes cell proliferation Opposes apoptosis Regulates differentiation	Activating mutation Increased cellular proliferation Inhibition of apoptosis
Human Epidermal Growth Factor Receptor 2 (HER-2)^[86]^[87]	Promotes cell prolifeartion Inhibition of apoptosis Regulates differentiation	Activating mutation Increased cellular proliferation Inhibition of apoptosis
Non-receptor tyrosine kinase Src^[88]^[89]	Involved in regulation of Gene transcription Angiogenesis Cellular adhesion Cellular proliferation	Activating mutation Increased angiogenesis Decreased cellular adhesion Increased tumor metastasis Increased cellular proliferation
Colony stimulating factor-1/fms^[1]^[90]^[91]	Increased macrophage survival Increased macrophage proliferation Increased macrophage differentiation	Activating mutation Stimulation of tumor cell proliferation Increased angiogenesis Promotes tumor invasion Increased metastasis Decreased anoikis
Insulin-like growth factor/receptor ILGF/ILGFR^[92]^[93]^[94]	Promotes growth Increased survival	Activating mutation Increased proliferation Enhanced survival Suppression of cell cycle regulators
k-ras^[95]^[96]	Cellular proliferation Cell survival	Activating mutation Increased proliferation Enhanced survival
b-raf^[97]^[98]	Cellular proliferation Cellular differentiation	Activating mutation Increased proliferation Enhanced growth
Transforming growth factor-β^[99]^[100]^[101]	May function as a tumor suppressor and a promoter Promotes growth arrest Maintains cellular homeostasis	Increased proliferation Decreased apoptosis Epithelial-to-mesenchymal transition Sustained angiogenesis Evasion of immune surveillance Metastasis
myc^[102]^[103]^[104]	Derives cellular proliferation Increased growth Cell-cycle mediator Inhibits apoptosis Stem-cell renewal	Activating mutation Increased proliferation Decreased apoptosis Increased metabolism in tumor cells
Cyclin D/Cdk4/6^[105]^[106]^[107]	Cell-cycle mediator Controls G1 length	Activating mutation Decreased G1 length Increased proliferation Increased angiogenesis
Cyclin E/Cdk2^[108]^[109]^[110]	Cellular proliferation Cell-cycle mediator Assembly of the pre-replication complex Promotes G0 to cell cycle entry Promotes G1 to S phase transition Decreased apoptosis	Activating mutation Increased cellular proliferation Impaired apoptosis Increased cellular survival
Cyclin B/Cdk1^[111]^[112]^[113]	Cell-cycle mediator promotes G2 to M phase transition	Activating mutation Increased cellular proliferation Promotes malignant transformation
p16^[114]^[115]^[116]	Member of the INK4 family of CDK inhibitors Inhibits Cyclin D/Cdk4/6 Decreased G1 to S phase transition	Lost or downregulated Decreased G1 length Increased proliferation Increased angiogenesis
p27 (kip-1)^[117]^[118]^[119]	Inhibitor of Cyclin E/Cdk2 Mediates cell cycle arrest Decreased G1 to S phase transition May act as oncogen and promote proliferation	Lost or dysregulated Increase in cell proliferation Impaired apoptosis
p21 (WAF-1)^[120]^[121]^[122]	Inhibits cyclin-dependant kinases Cell-cycle arrest Decreased proliferation Promotes cellular differentiation May inhibit/promote apoptosis May act as oncogen and promote proliferation	Lost or dysregulated Increase in cell proliferation Decreased cellular differentiation Decreased apoptosis Correlates positively tumour grade invasiveness aggressiveness
Nuclear factor-κB^[123]^[124]^[125]	A transcription factor involved in regulation of immune response to inflammation expression of cytokines, chemokines, and adhesion molecules cell cycle apoptosis May function as a tumor suppressor and a promoter	Dysregulated Increased angiogenesis Enhanced tumor growth Induces resistance to chemotherapy by acting as anti-apoptosis
NOEY(ARHI)^[126]^[127]^[128]^[129]	Inhibits cell growth Induces apoptosis Inhibits tumor cells migration through chemotaxis and haptotaxis	Inactivating mutation Enhanced tumor growth Decreased apoptosis Increased chances for metastasis
PIP3/Akt^[130]^[131]	Akt is activated by PIP3 and plays a role in regulation of cellular growth cell cycle progression regulation of glucose metabolism genome stability gene transcription protein synthesis neovascularization promotes cell survival by blocking apoptosis	Activating mutations Increased cellular proliferation Increased tumor cells survival Increased tumor cells migration Increased tumor cells invasion Chemotherapy resistance Decreased apoptosis May promote angiogenesis
PTEN^[132]^[133]^[134]	Suppresses Akt and thus regulates cell cycle, cellular growth and apoptosis Regulates self-renewal and differentiation of human stem cells Regulates oocyte growth and follicular activation Regulates chemotaxis of neutrophils Inhibit cell invasion and migration	Deletion or inactivating mutation Increased cellular proliferation Increased tumor cells survival Increased tumor cells migration Increased tumor cells invasion Decreased apoptosis
p53^[135]^[136]^[137]	A transcription factor that regulates cell cycle promotes DNA damage repair promotes apoptosis maintains genomic integrity	Loss results in DNA damage and carcinogenesis increased tumor cell growth and survival increased metastasis decreased apoptosis resistance to chemotherapy
BRCA1^[50]^[48]^[138]	A tumor suppressor that mediates double stranded DNA repair through homologous recombination pathway non-homologous end joining pathway Activates checkpoints in cell cycle Maintains genomic integrity	Mutations are responsible for hereditary breast & ovarian tumors Loss results in DNA damage and carcinogenesis increased tumor cell growth and survival
BRCA2^[50]^[48]^[138]	A tumor suppressor that mediates double stranded DNA repair through homologous recombination pathway Maintains genomic integrity Protects replication fork and replication fidelity	Mutations are responsible for hereditary breast & ovarian tumors Loss results in DNA damage and carcinogenesis increased tumor cell growth and survival Defects in maintenance the length of the nascent strand of DNA
MLH1/MSH2^[139]^[140]^[141]	Tumor suppressors that mediates DNA damage repair maintains genomic integrity possible regulation of cell cycle	Loss results in DNA damage and carcinogenesis increased survival resistance to chemotherapy chromosomal instability microsatellite instability (MSI) the cytosine phosphate guanine (CpG) island methylator phenotype (CIMP)
Fas ligand^[142]^[143]^[144]	Binds to Fas receptor and induces apoptosis Expressed mainly on T-lymphocytes May induce apoptosis in cancer cells and virus infected cells May also be involved in liver regeneration following partial hepatectomy neurite outgrowth	Most tumor cells are resistant to Fas-FasL mediated apoptosis Tumor cells express FasL to induce apoptosis in cytotoxic lymphocytes Promotes tumor cells survival Enhances tumor cells invasion Increased tumor cells migration
Human leukocyte antigen-G^[145]^[146]^[147]	Inhibits T-cell function through inhibiting proliferation causing cytotoxicity inducing apoptosis cytokine production in B lymphocytes inhibiting differentiation Inhibits proliferation and cytotoxicity of natural killer cells Promotes angiogenesis Inhibits chemotaxis	Promotes progression of cancer through evasion of immune response by inhibiting T-cell functions by inducing apoptosis and decreased proliferation inhibiting T-cell differentiation through various mechanisms Inhibits proliferation and cytotoxicity of natural killer cells Promotes angiogenesis Inhibits chemotaxis of cytotoxic cells
hTERT^[148]^[149]^[150]	Maintains telomeres length Promotes replication	Up-regulated in majority of human cancers Provides limitless replication ability to cancer cells
Vascular endothelial growth factor/Vascular endothelial growth factor receptor^[151]^[152]^[153]	Stimulates angiogenesis through increased endothelial cell survival Increased endothelial cell proliferation increased endothelial cell migration Increases vascular permeability May regulate fibroblasts in the stroma of tumors May effect tumor stem cells	Promotes angiogenesis Promotes tumor cells growth May initiate carcinogenesis Promotes invasion and metastasis of tumor cells
Interleukin-8^[154]^[155]^[156]	Chemokine produced to recruit leukocytes and myeloid-derived suppressor cells Promotes epithelial-to-mesenchymal transition Promotes infection resolution Promotes angiogenesis	Promotes epithelial-to-mesenchymal transition in tumor cells Promotes resistance to chemotherapy Tumor progression through immunosuppressive and pro-tumorigenic immune cells Promotes angiogenesis Promotes invasion and metastasis
EphA2^[157]^[158]^[159]	Promotes angiogenesis Plays a key role in development of Lens Inner ear Mammary glands Promotes kidney repair following injury Promotes bone remodeling bone remodeling	Over-expressed in ovarian epithelial cancer Promotes tumor initiation Promotes neo-vascularization Promotes tumor invasion Promotes metastasis
Matrix metalloproteinases^[160]^[161]^[162]	Proteases that degrade tissues, matrix and other proteins and play a role in bone modeling and remodeling mammary development blood vessels remodeling a variety of other tissues such as tracheal tube Promotes inflammation through enzymatic activation	Over-expressed in ovarian epithelial cancer Promotes tumor invasion through degradation of extra-cellular matrix Promotes metastasis through degradation of extra-cellular matrix May have a role in tumor initiation and angiogenesis
αvβ3^[163]^[164]^[165]	One of the most important mediator of angiogenesis promotes smooth muscle cells migration and proliferation	Promotes angiogenesis Promotes survival
Focal adhesion kinase (FAK)^[166]^[167]^[168]	Promotes endothelial cells migration May play a role in integrin-dependent cell survival signal Inhibits apoptosis Enhances cell motility	Promotes angiogenesis Promotes tumor cells survival Inhibits apoptosis Promotes tumor metastasis
E-cadherin^[169]^[170]^[171]	One of the most important promoter of cell-cell adhesion Play critical role in formation and maintenance of epithelia, and tissue formation	Loss or mutations results in epithelial–mesenchymal transition decreased cell-cell adhesion tumor cells invasion metastasis

Hereditary Epithelial Ovarian Carcinoma: An overview of Hereditary Syndromes and the Genetic Mutations

Hereditary Breast and Ovarian Cancer (HBOC)

Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant disorder caused by mutations in BRCA1 and BRCA2 genes that are responsible for DNA repair in homologous recombination pathway.^[47]^[50]
Individuals with this disorder are at risk of developing breast (lifetime risk is 30-80%) and ovarian cancer (lifetime risk is 30-50%), along with other malignancies such as pancreatic, stomach, laryngeal, fallopian tube and prostate cancer.^[47]^[50]
The reason for increased susceptibility to ovarian and epithelial cancer is not fully understood but but may be explained by repression of the transcription of hormone-mediated signalling factors or production of reactive oxygen species during menstrual cycle mediating DNA damage.^[50]^[172]^[173]


Malignancies associated with BRCA mutations (Hereditary breast and ovarian cancer syndrome)^[174]
Breast cancer (male and female) Ovarian cancer Fallopian tube carcinoma Primary papillary carcinoma of the peritoneum Prostate cancer Uterine body cancer Cervical cancer Pancreatic cancer Gall bladder cancer Bile duct cancer Stomach cancer Melanoma

Lynch Syndrome

Lynch syndrome (LS), also known as hereditary nonpolyposis colon cancer (HNPCC), is characterized by germline mutations in DNA mismatch repair genes MLH1, MSH2, MSH6, MLH3, and PMS2.^[47]^[45]^[49]
A simplified version of repair mechanism by mismatch repair genes products is described below:^[49]^[56]

MutS homologs (MSHs) recognize the DNA mismatch → MutS homologs (MSHs) recruit MutL homologs (MLHs) → excision of mismatched DNA → DNA polymerase re-synthesizes DNA.

Accounted for 10-15% of all ovarian cancers, this syndrome is caused by inherited mutation in one allele and then loss of second allele (secondary hit).^[47]^[175]
The most common malignancies in Lynch syndrome are colorectal carcinoma and gynecological cancers, endometrial carcinoma being the most common among gynecological malignancies followed by ovarian carcinoma.^[175]
Other malignancies that have been observed in lynch syndrome are gastric cancer, small bowel malignancies, hepatobiliary epithelial carcinoma, uroepithelial epithelial carcinoma and brain tumors.^[175]^[176]

Genetic variation in Lynch syndrome.^[177]

Li-Fraumeni Syndrome

Li-Fraumeni Syndrome is an autosomal dominant disorder caused by germline mutation in TP53, the most mutated gene in human cancers. The most common of the mutations are missense mutations.^[57]^[58]
TP53 encodes for a transcription factor that responds to various cell signals and is a major regulator of the cell cycle. It is involved in variety of cellular functions such as cellular proliferation and cell cycle, apoptosis, and stability & integrity of the genome.^[59]^[58]
Mutations in TP53 resulting defective or decreased p53 are not only implicated in pathogenesis but also impact prognosis, causing worse survival rate among the individuals with the mutations.^[59]^[178]
These mutations are most commonly observed in epithelial ovarian cancer (47%), colorectal carcinoma (43%), head/neck cancer (42%), and esophageal cancer (41%). Breast cancer, sarcoma and brain, and adrenocortical carcinoma account for majority of the tumors encountered in Li-Fraumeni syndrome.^[59]^[179]

Site-Specific Ovarian Cancer

A term used to describe families in which there are several relatives with epithelial ovarian cancer but no other co-existent malignancies that are associated with other hereditary syndromes associated with epithelial ovarian cancer.^[180]
A hypothesis is that it is caused by gen/genes that are yet to be identified. Site-specific ovarian cancer appears to be transmitted in autosomal-dominant fashion in some families but some studies have suggested the risk to be as low as 5%.^[180]^[181]

Cowden Syndrome

An autosomal-dominant syndrome , caused by mutations in PTEN gene, has been associated with a variety of neoplastic/non-neoplastic lesions and clinical manifestations throughout the body including:^[180]^[182]^[183]
- Epithelial ovarian cancer
- Hamartomatous lesions of skin and organs
- Macrocephaly
- Breast cancer
- Thyroid cancer
- Endometrial cancer

RAD51

RAD51 is a recombinase that binds with eight BRC repeats of BRCA2. This allows RAD51 to be recruited to double stranded DNA breaks, an essential step in homologous recombination double stranded DNA repair.^[50]^[52]^[53]^[57]
Some studies have suggested risk for developing ovarian cancer in RAD51 mutations is as high as six-fold. There is also an increased risk for developing breast cancer.^[57]^[184]^[185]

PALB2

Partner and localizer of BRCA2 (PALB2) physically connects BRCA1 and BRCA2 through N-terminal coiled-coil domain and the C terminus. This BRCA2 interacting protein plays an essential role in DNA repair.^[50]^[54]^[55]
The association of PALB2 with ovarian cancer has not be fully established but an increased risk for breast cancer, pancreatic cancer and ovarian cancer has been observed in some studies.^[45]^[186]^[187]

CHEK2

CHEK2 gene encodes for a protein called checkpoint kinase 2 (CHK2). It interacts with other regulators and tumor suppressors such as TP53 to play a role in tumor suppression through cell-cycle regulation and apoptosis.^[188]^[189]
There are conflicting results regarding association of CHEK2 with ovarian cancers. Some studies have suggested no association but the limitations were observed because of focus on only certain allelic mutations in CHEK2.^[45]^[190]

Mre11 Complex

Mre11 Complex is involved in DNA repair and comprises of meiotic recombination 11 (MRE11), RAD50 and Nijmegen breakage syndrome 1 (NBS1; also known as nibrin).^[45]^[191]
This complex plays an essential role in homologous recombination mediated DNA repair, non-homologous end-joining (NHEJ) and alternative non-homologous end-joining (A-NHEJ) pathways, all involved in double stranded DNA repair.^[191]^[192]
Some studies have suggested an increased susceptibility to ovarian and breast cancers in hereditary mutations in Mre11 complex.^[45]^[193]

BARD1

This gene encodes for a peptide that interacts with BRCA1 and forms a heterodiamer that plays a role in homologous recombination mediated repair of double stranded DNA breaks.^[194]^[195]
Mutations in BARD1 have been associated with breast and ovarian cancer.^[45]^[196]

BRIP1

BRCA1-interacting protein 1 (BRIP1) encodes for a helicase that interacts with BRCA1 in homologous recombination mediated repair of double stranded DNA breaks.^[197]^[198]
Mutation in BRIP1 gene association with familial ovarian cancer have been demonstrated in some studies. There also been proposed risk for breast cancer but it has yet to be established.^[198]^[199]

An attempt to explain the origin of carcinogenesis in sporadic epithelial carcinoma


Proposed hypothesis	Proposed Mechanism	For	Against
Incessant ovulation^[1]^[200]^[201]^[202]^[203]^[204]	Every ovulatory cycle leads to epithelial injury and resultant repairs make cells more susceptible to mutations	Increased incidences of ovarian epithelial cancers in advanced age (increased number of cycles) Factors that decrease ovulatory cycles such as oral contraceptive use, pregnancy and breast-feeding decrease the risk for ovarian epithelial cancer	Progesterone only oral contraceptives do not inhibit ovulatory cycles but still decrease the risk for ovarian epithelial cancers Polycystic ovarian syndrome (PCOS) decreases the number of ovulatory cycles but increases the risk for ovarian epithelial cancer.
Gonadotropins^[1]^[204]^[205]^[206]^[207]^[208]^[209]	Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and human chorionic gonadotropin stimulate ovarian epithelial cells proliferation Resultant increased mitotic activity make cells more susceptible to mutations	Higher incidences of epthelial ovarian cancers in women taking infertility drugs in some studies Polycystic ovarian syndrome (PCOS) and infertility increase the risk for ovarian epithelial cancers Progesterone only oral contraceptives decrease the risk for ovarian epithelial cancers Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are shown to increase cell proliferation in some studies Up-regulation of Cox-1 and Cox-2 and resultant increase in PGE2 by follicle-stimulating hormone (FSH) and luteinizing hormone (LH) has been observed Up-regulation of potential oncogenes in vitro such as EGFR, HER-2, and c-myc, cyclin G2, Meis-1, β-catenin, β-1 integrin, and IGF-1 by Follicle-stimulating hormone (FSH) receptor over-expression	Some studies suggest that infertility, rather than gonadotropin drugs treatment, increases the susceptibility to epithelial ovarian cancers No concrete linkage of gonadotropins to malignant transformation of surface epithelial cells of ovaries Proposed hypothesis of gonadotropin role in tumor cell growth and survival rather than origin
Hormonal influence^[1]^[203]^[204]^[210]^[211]^[212]	Androgens confer greater risk to epithelial ovarian cancer while progesterone decreases the rik	Conditions that result in androgenic excess such as Polycystic ovarian syndrome (PCOS), hirsutism, and acne have been shown to increase the risk for epithelial ovarian cancer Andorgens can stimulate cellular proliferation (androgens are are thought to be pre-dominant in ovarian inclusion cysts) Progesterone only oral contraceptives decrease the risk for ovarian epithelial cancers, possibly through decreased androgens	No concrete linkage of androgens to malignant transformation of surface epithelial cells of ovaries No evidence of androgens and their precursors affecting cancer cells growth
Inflammation^[1]^[208]^[213]^[214]	Cytokines and inflammatory cells are involved in ovulation and repair and increase susceptibility to mutations and carcinogenesis	Non-steroidal anti-inflammatory drugs (NSAIDS) and Aminosalicylic acid (ASA) are thought to decrease the risk for epithelial ovarian cancer Chemicals that cause inflammation such as talc and asbestos are shown to be associated with an increased risk for epithelial ovarian cancer Inflammatory pathways and mediators have been observed in tumor pathogenesis and tumor micro-environment	No established linkage between talc and asbestos with pathogenesis of epithelial ovarian cancers in animal studies

Obesity: A Risk Factor for Epithelial Cancer

A British study comprising of 1.2 million women found that incidences of epithelial ovarian cancer were higher among women with BMI >30 as compared to women with normal BMI, with risk increasing with incremental increase in BMI. A meta-analysis conducted Olsen et al.also found an increase risk for epithelial ovarian cancer in obese women.^[215]^[216]^[217]
It has been hypothesized that waist to hip ratio provides a better risk determination for epithelial ovarian cancer because of more accuracy in assessing true visceral fat deposition but remains to be validated.^[215]^[218]
The time at which women develop obesity during their life may be a key factor for increased risk for epithelial ovarian cancer. Multiple studies indicate that increased BMI in adolescence and/or early adulthood may confer a greater risk for developing epithelial ovarian cancer.^[215]^[219]^[220]
Another study postulates that duration and severity of obesity is also associated with increased risk for epithelial ovarian cancer and few others postulate that association of obesity with epithelial ovarian cancer is greater in premenopausal women than post-menopausal.^[215]^[216]^[221]
Another meta-analysis demonstrated that obesity is associated with not only an increased risk for epithelial ovarian cancer but also with decrease in overall survival and ovarian-cancer specific survival. Another study also showed an increase in ovarian cancer- related mortality in obese women.^[215]^[222]^[223]

Diabetes Mellitus and The Risk of Epithelial Ovarian Cancer

While conflicting data is present for association of diabetes mellitus and an increased risk for epithelial ovarian cancer, multiple studies, however, demonstrated diabetes as an independent risk factor for increased mortality in epithelial ovarian cancer.^[215]^[224]^[225]^[226]^[227]

Findings in some studies indicate a greater risk for epithelial ovarian cancer in diabetic women while some suggest an increased risk only in pre-menopausal women, and some suggest no increase in risk for epithelial ovarian cancer at all.^[215]^[224]^[225]^[226]

Metabolic Syndrome and the Risk of Epithelial Ovarian Cancer

The case for metabolic syndrome to be associated with an increased risk for epithelial ovarian cancer is similar to that of diabetes mellitus. There has been a fewer studies on association between metabolic syndrome and epithelial ovarian cancer and the results are conflicting with some found an increased risk for epithelial ovarian cancer in women with metabolic syndrome while some found no association.^[215]^[228]^[229]
But an association of metabolic syndrome with increased ovarian cancer-related mortality was found in these studies. These studies however had limitation of lack of racial diversity because the study sample comprised only of Caucasian women.^[215]^[229]

Pathogenesis of Epithelial Ovarian Cancer Associated with Metabolic Abnormalities

The work on mechanisms linking metabolic abnormalities to epithelial ovarian cancer is not yet complete and the way by which these abnormalities confer a greater risk for epithelial ovarian cancer is not well-understood but several theories have been put forward.
The most significant of these theories include role of cytokines and adipokines, immune cells, and aberrant signaling pathways in association with increased risk for epithelial ovarian cancer in women with metabolic derangement.

Cytokines and Adipokines


The role of cytokines and adipokines in epithelial ovarian cancer
Cytokines and adipokines	Association with metabolic abnormalities	Proposed mechanism in initiation and progression of epithelial ovarian cancer
Tissue necrosis factor-α^[215]^[230]^[231]^[232]	Produced by immune cells (macrophages), tumor cells and fat cells Shown to be elevated in obesity and diabetes mellitus	Promotes matrix metalloproteinases that contribute to carcinognesis and increased risk for tumor cell invasion and metastasis Promotes tumor cells growth by acting as paracrine and autocrine growth factor Promotes angiogenesis that contribute to tumor progression Promotes cell survival Promotes cell proliferation Inhibits apoptosis Acts to decrease adiponectin levels by decreasing its production Promotes aromatase expression in adipose tissues Promotes insulin resistance Promotes inflammation A positive correlation of tissue necrosis factor-α levels with tumor grade of epithelial ovarian cancer Elevated levels shown to be associated with decreased overall survival
Leptin^[215]^[233]^[234]^[235]^[236]	Produced by adipocytes Shown to be elevated in obesity and produced by tumor cells Leptin receptors expressed by tumor cells	Inhibits natural killer function by decreasing toxicity towards tumor cells perforin production interferon-γ secretion Promotes secretion of interleukin-6 and tissue necrosis factor-α by monocytes Promotes tumor cells growth and invasion Promotes resistance to apoptosis Promotes tumor cells proliferation Promotes expression of cyclin-D that increases tumor cells growth and survival Promotes tumor cells migration Shown to decrease progression-free survival in epithelial ovarian tumors
IL-6^[215]^[235]^[237]	Produced by immune cells (macrophages), tumor cells and fat cells Shown to be elevated in obesity and diabetes mellitus Reactive oxygen species associated with an increased level of interlekin-6	Promotes angiogenesis Associated with increased aromatase that leads to elevated levels of estrogen Inhibits apoptosis by increasing expression of anti-apoptotic proteins Promotes resistance to chemotherapy Promotes inflammation Associated with increased levels of C-reactive protein Response prediction to bevacizumab therapy
C reactive protein (CRP)^[215]^[232]	Produced by liver Shown to be elevated in obesity and diabetes mellitus	Shown to be associated with an increased risk for developing epithelial ovarian cancer
Monocyte chemotactic protein-1 (MCP-1)^[215]^[233]^[238]	Produced by ovarian tumor cells Induced by hypoxia inducible factor (levels elevated in obesity) Elevated levels observed in obesity	Promotes monocytes recruitment Associated with increased density of tumor associated macrophages May play a role in angiogenesis
Adiponectin^[215]^[218]^[239]^[240]	Produced by mature fat cells Shown to be decreased in obesity and diabetes mellitus	Anti-tumor effects lost/decreased in obesity and diabetes mellitus that include insulin sensitivity Inhibition of inflammation inhibition of tumor growth inhibition of angiogenesis inhibition of tissue necrosis factor-α signaling

Immune Cells

Immune cells may have a pro or anti-tumor effect, depending on the cell type. Metabolic risk factors may alter these cell types and their functions to have a promoter effect in initiation and progression of epithelial ovarian tumors.^[215]
The table below provides a short overview of possible role of immune cells in pathogenesis of epithelial ovarian tumors.^[215]


The role of immune cells in epithelial ovarian cancer
Cell type	Link with metabolic risk factors	Possible role in pathogenesis
Dendritic cells^[241]^[242]^[243]	Tumor stroma-derived factor 1 (SDF-1) recruits dendritic cells	Interleukin 10 by tumor cells leads to alteration in dendritic cells differentiation These specific subtypes induced by tumor cells cytokines are less efficient in T-cells activation Interact with programmed death-ligand 1 (PD-L1) to decrease T-cells effector function
Macrophages^[238]^[244]^[245]^[246]^[247]	Two populations: (1) M1 → classically activated tumor associated macrophages (2) M2 → alternatively activated tumor associated macrophages Studies indicate decreased M1 subpopulation in obese patients leading to ↓ M1/M2 ratio Interferon gamma induce differentiation of macrophages into M1 subpopulation Differentiation of macrophages into M2 subpopulation is possibly promoted by transforming growth factor-beta interleukin-4 interleukin-10 interleukin-13 colony stimulating factor-1	M1 inhibit tumor progression promote inflammation through production of cytokines cytotoxic to tumor cell produce and release reactive oxygen species (ROS) M2 promote tumor cells growth promote angiogenesis promote invasion and metastasis promote tissue repair inhibits immune system produce C-C motif chemokine 22 (CCL22)
Natural killer cells^[248]^[249]	Leptin may inhibit cytotoxic activity and interferon-γ production by natural killer cells Mucin 16, Cell Surface Associated (MUC16) suppresses natural killer cells function	Increased natural killer cells activity in peripheral blood → increased progression free survival Higher number of natural killer cells in peritoneal/pleural fluids → poor prognosis
B-cells^[247]^[250]^[251]	Animal model studies indicate an up to threefold increase in B cells population in tumor cells in obese patients	Higher B cells tumor population associated with poorer prognosis Promote angiogenesis
T-cells^[248]^[252]^[253]^[254]	Interaction with programmed death-ligand 1 (PD-L1) inhibits CD4+ and CD8+ cells function Transforming growth factor-β inhibits cytotoxic function of CD8+ cells C-C motif chemokine 22 (CCL22) recruits regulatory T cells to the tumor	CD4+ cells produce interleukin-17 that may have an anti-tumor role CD8+ cells increased number is associated with increased survival Regulatory T-cells release interleukin-10 and transforming growth factor-β that inhibit anti-tumor function of T-cells inhibit cytotoxic function of CD8+ T cells

Hormones, Signaling Pathways in Pathogenesis of Epithelial Ovarian Cancer and Their Link to Metabolic Risk Factors

Hormones and signaling pathways that may play a role in pathogenesis of epithelial ovarian cancer with link to metabolic abnormalities are summarized below in table:^[215]


Possible role of hormones and signal transduction pathways in relation to metabolic abnormalities
Hormone	Link with metabolic risk factors	Possible role in pathogenesis
Hypoxia inducible factor (HIF)^[233]^[230]^[255]^[256]	Increased in obesity due to relative hypoxia	Promotes growth and survival by increased production/expression of interleukin-6 tissue necrosis factor monocyte chemoattractant protein-1 (MCP-1) erythropoietin vascular endothelial growth factor and vascular endothelial growth factor receptors glucose transporters glycolytic enzymes Promotes inflammation through increased expression of cytokines and recruitment of macrophages Leads to increased C-X-C chemokine receptor type 4 (CXCR-4) that leads to increased density of tumor associated macrophages Promotes angiogenesis Promotes pro-fibrotic pathway, resulting in altered extra-cellular matrix
Vascular endothelial growth factor (VEGF)^[247]^[257]	Increased levels observed in obesity	Promotes angiogenesis Promotes tumor cells growth Promotes metastasis
Insulin-like growth factor 1 (IGF-1)^[233]^[225]^[258]^[259]	Increased levels observed in obesity Increased levels in diabetes mellitus patients	Promotes tumor cells growth Promotes angiogenesis Inhibits apoptosis Decreases sex hormone binding globulin, leading to increased levels of biologically available estrogen Associated with increased levels of hypoxia inducible factor (HIF) Correlates negatively with survival
Estrogen^[233]^[260]^[261]	Increased levels observed in obesity	Promotes tumor cells growth through action as a mitogen Associated with increased expression of insulin-like growth factor 1 (IGF-1) receptors

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@@ Line 1: / Line 1: @@
 __NOTOC__
 {{Epithelial ovarian tumors}}
 {{CMG}}{{AE}}{{HMHJ}}
 ==Overview==
+Surface epithelium of ovaries (OSE), once mistakenly referred as germinal epithelium, consists of single layer of flat to cuboidal epithelial cells. It is characterized by keratin types found in simple epithelium and functions in exchange between peritoneal cavity and the ovaries in addition to ovarian cycle. During embryonic development, surface epithelium of ovaries is a part of celomic epithelium. The future surface epithelium of ovaries then forms part of gonadal blastema and then undergoes a transformation cycle, multilayered papillary epithelium develops from simple flat to cuboidal epithelium but reverts back to simple flat to cuboidal epithelium by term. The most important functions of human surface epithelium of ovaries are its role in transport and exchange between peritoneal cavity and ovaries, and its function in repair and rupture during ovulation. Ovarian surface epithelium undergo epithelio-mesenchymal transformation to replace ovarian stroma in ovulatory repair. The previous proposition regarding the origin of epithelial ovarian cancers was that these tumors originated from surface epithelium of the ovaries and the neoplastic and metaplastic changes led to their differentiation into various histological subtypes such as serous tumors, clear cell carcinoma and endometrioid tumors. But apparent consistencies in this theory has led to development of alternate theories such as origin of neoplastic cells from fallopian tubes and endometrium.
-== Surface epithelium of ovaries ==
+==Pathophysiology==
-Surface epithelium of ovaries (OSE), once mistakenly referred as germinal epithelium, consists of single layer of flat to cuboidal epithelial cells. It is characterized by keratin types found in simple epithelium and functions in exchange between peritoneal cavity and the ovaries in addition to ovarian cycle.
 === Embryogenesis ===
+'''Celomic epithelium → Peritoneal mesothelium surrounding the ovary → Metaplasia to ovarian surface epithelium'''<ref name="pmid21761359">{{cite journal |vauthors=Saad AF, Hu W, Sood AK |title=Microenvironment and pathogenesis of epithelial ovarian cancer |journal=Horm Cancer |volume=1 |issue=6 |pages=277–90 |date=December 2010 |pmid=21761359 |pmc=3199131 |doi=10.1007/s12672-010-0054-2 |url=}}</ref><ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref>
 * During embryonic development, surface epithelium of ovaries is a part of celomic epithelium.<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref>
 * Celomic epithelium itself is derived from mesothelium and forms lining of intraembryonic celom.<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref>
@@ Line 16: / Line 14: @@
 * Ovarian surface epithelium has also been postulated to give rise or form a part of ovarian granulosa cells during embryonic development.<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref><ref name="pmid3348150">{{cite journal |vauthors=Yoshinaga K, Hess DL, Hendrickx AG, Zamboni L |title=The development of the sexually indifferent gonad in the prosimian, Galago crassicaudatus crassicaudatus |journal=Am. J. Anat. |volume=181 |issue=1 |pages=89–105 |date=January 1988 |pmid=3348150 |doi=10.1002/aja.1001810110 |url=}}</ref>
-=== Structural characteristics of ovarian surface epithelium in human adults ===
+=== Structural Characteristics of Ovarian Surface Epithelium in Adults ===
 {| class="wikitable"
 |+
-!Cell type
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Cell type
-!Surface expression
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Surface expression
-!Intercellular connection
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Intercellular connection
-!Basement membrane
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Basement membrane
 |-
 |
 * Single layer
 * squamous-to-cuboidal epithelium
 |
 * Keratin
 * Mucin antigen MUC1
@@ Line 37: / Line 35: @@
 * Integrins
 * Cadherins
 |
 * Loosely attached
 * Tunica albuginea that is less conspicuous of its testicular counterpart
@@ Line 55: / Line 53: @@
 * The differentiation of surface epithelium of ovaries is, however,  different from other epithelia because of its ability of differentiate into ectopic epithelium such as that of epithelium formed by Mullerian ducts.<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref>
-=== Role of hormones and growth factors on surface epithelium ===
+=== Role of Hormones and Growth Factors on Surface Epithelium ===
 {| class="wikitable"
 |+
 |-
-|Gonadotropin-releasing hormone
+| style="background:#DCDCDC;" align="center" + | Gonadotropin-releasing hormone
 and gonadotropin''s''<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid10399050">{{cite journal |vauthors=Davies BR, Finnigan DS, Smith SK, Ponder BA |title=Administration of gonadotropins stimulates proliferation of normal mouse ovarian surface epithelium |journal=Gynecol. Endocrinol. |volume=13 |issue=2 |pages=75–81 |date=April 1999 |pmid=10399050 |doi= |url=}}</ref>
@@ Line 65: / Line 63: @@
 * Cell proliferation
 |-
-|Epidermal growth factor (EGF)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid2450877">{{cite journal |vauthors=Siemens CH, Auersperg N |title=Serial propagation of human ovarian surface epithelium in tissue culture |journal=J. Cell. Physiol. |volume=134 |issue=3 |pages=347–56 |date=March 1988 |pmid=2450877 |doi=10.1002/jcp.1041340305 |url=}}</ref><ref name="pmid2003535">{{cite journal |vauthors=Rodriguez GC, Berchuck A, Whitaker RS, Schlossman D, Clarke-Pearson DL, Bast RC |title=Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. II. Relationship between receptor expression and response to epidermal growth factor |journal=Am. J. Obstet. Gynecol. |volume=164 |issue=3 |pages=745–50 |date=March 1991 |pmid=2003535 |doi= |url=}}</ref><ref name="pmid10706107">{{cite journal |vauthors=Evangelou A, Jindal SK, Brown TJ, Letarte M |title=Down-regulation of transforming growth factor beta receptors by androgen in ovarian cancer cells |journal=Cancer Res. |volume=60 |issue=4 |pages=929–35 |date=February 2000 |pmid=10706107 |doi= |url=}}</ref>
+| style="background:#DCDCDC;" align="center" + | Epidermal growth factor (EGF)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid2450877">{{cite journal |vauthors=Siemens CH, Auersperg N |title=Serial propagation of human ovarian surface epithelium in tissue culture |journal=J. Cell. Physiol. |volume=134 |issue=3 |pages=347–56 |date=March 1988 |pmid=2450877 |doi=10.1002/jcp.1041340305 |url=}}</ref><ref name="pmid2003535">{{cite journal |vauthors=Rodriguez GC, Berchuck A, Whitaker RS, Schlossman D, Clarke-Pearson DL, Bast RC |title=Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. II. Relationship between receptor expression and response to epidermal growth factor |journal=Am. J. Obstet. Gynecol. |volume=164 |issue=3 |pages=745–50 |date=March 1991 |pmid=2003535 |doi= |url=}}</ref><ref name="pmid10706107">{{cite journal |vauthors=Evangelou A, Jindal SK, Brown TJ, Letarte M |title=Down-regulation of transforming growth factor beta receptors by androgen in ovarian cancer cells |journal=Cancer Res. |volume=60 |issue=4 |pages=929–35 |date=February 2000 |pmid=10706107 |doi= |url=}}</ref>
 |
 * Cell proliferation and differentiation
 * Increased survival
 |-
-|Steroids<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid11159828">{{cite journal |vauthors=Kang SK, Choi KC, Tai CJ, Auersperg N, Leung PC |title=Estradiol regulates gonadotropin-releasing hormone (GnRH) and its receptor gene expression and antagonizes the growth inhibitory effects of GnRH in human ovarian surface epithelial and ovarian cancer cells |journal=Endocrinology |volume=142 |issue=2 |pages=580–8 |date=February 2001 |pmid=11159828 |doi=10.1210/endo.142.2.7982 |url=}}</ref><ref name="pmid7988745">{{cite journal |vauthors=Liu Y, Lin L, Zarnegar R |title=Modulation of hepatocyte growth factor gene expression by estrogen in mouse ovary |journal=Mol. Cell. Endocrinol. |volume=104 |issue=2 |pages=173–81 |date=September 1994 |pmid=7988745 |doi= |url=}}</ref>
+| style="background:#DCDCDC;" align="center" + | Steroids<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid11159828">{{cite journal |vauthors=Kang SK, Choi KC, Tai CJ, Auersperg N, Leung PC |title=Estradiol regulates gonadotropin-releasing hormone (GnRH) and its receptor gene expression and antagonizes the growth inhibitory effects of GnRH in human ovarian surface epithelial and ovarian cancer cells |journal=Endocrinology |volume=142 |issue=2 |pages=580–8 |date=February 2001 |pmid=11159828 |doi=10.1210/endo.142.2.7982 |url=}}</ref><ref name="pmid7988745">{{cite journal |vauthors=Liu Y, Lin L, Zarnegar R |title=Modulation of hepatocyte growth factor gene expression by estrogen in mouse ovary |journal=Mol. Cell. Endocrinol. |volume=104 |issue=2 |pages=173–81 |date=September 1994 |pmid=7988745 |doi= |url=}}</ref>
 |
 * Decreased expression of GnRH receptors (estrogen)
@@ Line 77: / Line 75: @@
 * May have direct effect on proliferation stimulation
 |-
-|Fibroblast growth factor (FGF)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid1381547">{{cite journal |vauthors=Basilico C, Moscatelli D |title=The FGF family of growth factors and oncogenes |journal=Adv. Cancer Res. |volume=59 |issue= |pages=115–65 |date=1992 |pmid=1381547 |doi= |url=}}</ref>
+| style="background:#DCDCDC;" align="center" + | Fibroblast growth factor (FGF)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid1381547">{{cite journal |vauthors=Basilico C, Moscatelli D |title=The FGF family of growth factors and oncogenes |journal=Adv. Cancer Res. |volume=59 |issue= |pages=115–65 |date=1992 |pmid=1381547 |doi= |url=}}</ref>
 |
 * Cell proliferation
 * Increased survival
 |-
-|Platelet-derived growth factor (PDGF)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid9784315">{{cite journal |vauthors=Dabrow MB, Francesco MR, McBrearty FX, Caradonna S |title=The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium |journal=Gynecol. Oncol. |volume=71 |issue=1 |pages=29–37 |date=October 1998 |pmid=9784315 |doi=10.1006/gyno.1998.5121 |url=}}</ref>
+| style="background:#DCDCDC;" align="center" + | Platelet-derived growth factor (PDGF)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid9784315">{{cite journal |vauthors=Dabrow MB, Francesco MR, McBrearty FX, Caradonna S |title=The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium |journal=Gynecol. Oncol. |volume=71 |issue=1 |pages=29–37 |date=October 1998 |pmid=9784315 |doi=10.1006/gyno.1998.5121 |url=}}</ref>
 |
 * Cell proliferation
 |-
-|Tissue necrosis factor-α (TNF-α)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid1550178">{{cite journal |vauthors=Wu S, Rodabaugh K, Martinez-Maza O, Watson JM, Silberstein DS, Boyer CM, Peters WP, Weinberg JB, Berek JS, Bast RC |title=Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-1, interleukin-6, and tumor necrosis factor-alpha |journal=Am. J. Obstet. Gynecol. |volume=166 |issue=3 |pages=997–1007 |date=March 1992 |pmid=1550178 |doi= |url=}}</ref><ref name="pmid8385577">{{cite journal |vauthors=Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB, Bast RC |title=Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression |journal=Cancer Res. |volume=53 |issue=8 |pages=1939–44 |date=April 1993 |pmid=8385577 |doi= |url=}}</ref>
+| style="background:#DCDCDC;" align="center" + | Tissue necrosis factor-α (TNF-α)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid1550178">{{cite journal |vauthors=Wu S, Rodabaugh K, Martinez-Maza O, Watson JM, Silberstein DS, Boyer CM, Peters WP, Weinberg JB, Berek JS, Bast RC |title=Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-1, interleukin-6, and tumor necrosis factor-alpha |journal=Am. J. Obstet. Gynecol. |volume=166 |issue=3 |pages=997–1007 |date=March 1992 |pmid=1550178 |doi= |url=}}</ref><ref name="pmid8385577">{{cite journal |vauthors=Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB, Bast RC |title=Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression |journal=Cancer Res. |volume=53 |issue=8 |pages=1939–44 |date=April 1993 |pmid=8385577 |doi= |url=}}</ref>
 |
 * Cell proliferation
 * Increased TNFα expression
 |-
-|Transfroming growth factor β (TGF-β)<ref name="pmid1536252">{{cite journal |vauthors=Berchuck A, Rodriguez G, Olt G, Whitaker R, Boente MP, Arrick BA, Clarke-Pearson DL, Bast RC |title=Regulation of growth of normal ovarian epithelial cells and ovarian cancer cell lines by transforming growth factor-beta |journal=Am. J. Obstet. Gynecol. |volume=166 |issue=2 |pages=676–84 |date=February 1992 |pmid=1536252 |doi= |url=}}</ref>
+| style="background:#DCDCDC;" align="center" + | Transfroming growth factor β (TGF-β)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid1536252">{{cite journal |vauthors=Berchuck A, Rodriguez G, Olt G, Whitaker R, Boente MP, Arrick BA, Clarke-Pearson DL, Bast RC |title=Regulation of growth of normal ovarian epithelial cells and ovarian cancer cell lines by transforming growth factor-beta |journal=Am. J. Obstet. Gynecol. |volume=166 |issue=2 |pages=676–84 |date=February 1992 |pmid=1536252 |doi= |url=}}</ref>
 |
 * Decreased growth
 |-
-|Hepatocyte growth factor (HGF)<ref name="pmid10684788">{{cite journal |vauthors=Parrott JA, Skinner MK |title=Expression and action of hepatocyte growth factor in human and bovine normal ovarian surface epithelium and ovarian cancer |journal=Biol. Reprod. |volume=62 |issue=3 |pages=491–500 |date=March 2000 |pmid=10684788 |doi= |url=}}</ref><ref name="pmid9112378">{{cite journal |vauthors=Gulati R, Peluso JJ |title=Opposing actions of hepatocyte growth factor and basic fibroblast growth factor on cell contact, intracellular free calcium levels, and rat ovarian surface epithelial cell viability |journal=Endocrinology |volume=138 |issue=5 |pages=1847–56 |date=May 1997 |pmid=9112378 |doi=10.1210/endo.138.5.5137 |url=}}</ref>
+| style="background:#DCDCDC;" align="center" + | Hepatocyte growth factor (HGF)<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid10684788">{{cite journal |vauthors=Parrott JA, Skinner MK |title=Expression and action of hepatocyte growth factor in human and bovine normal ovarian surface epithelium and ovarian cancer |journal=Biol. Reprod. |volume=62 |issue=3 |pages=491–500 |date=March 2000 |pmid=10684788 |doi= |url=}}</ref><ref name="pmid9112378">{{cite journal |vauthors=Gulati R, Peluso JJ |title=Opposing actions of hepatocyte growth factor and basic fibroblast growth factor on cell contact, intracellular free calcium levels, and rat ovarian surface epithelial cell viability |journal=Endocrinology |volume=138 |issue=5 |pages=1847–56 |date=May 1997 |pmid=9112378 |doi=10.1210/endo.138.5.5137 |url=}}</ref>
 |
 * Decreased cellular adhesion
 * Increased survival and growth
 |-
-|''Cytokines''<ref name="pmid7691194">{{cite journal |vauthors=Ziltener HJ, Maines-Bandiera S, Schrader JW, Auersperg N |title=Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium |journal=Biol. Reprod. |volume=49 |issue=3 |pages=635–41 |date=September 1993 |pmid=7691194 |doi= |url=}}</ref><ref name="pmid8824555">{{cite journal |vauthors=Marth C, Zeimet AG, Herold M, Brumm C, Windbichler G, Müller-Holzner E, Offner F, Feichtinger H, Zwierzina H, Daxenbichler G |title=Different effects of interferons, interleukin-1beta and tumor necrosis factor-alpha in normal (OSE) and malignant human ovarian epithelial cells |journal=Int. J. Cancer |volume=67 |issue=6 |pages=826–30 |date=September 1996 |pmid=8824555 |doi=10.1002/(SICI)1097-0215(19960917)67:6<826::AID-IJC12>3.0.CO;2-# |url=}}</ref>
+| style="background:#DCDCDC;" align="center" + | ''Cytokines''<ref name="pmid11294827">{{cite journal |vauthors=Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC |title=Ovarian surface epithelium: biology, endocrinology, and pathology |journal=Endocr. Rev. |volume=22 |issue=2 |pages=255–88 |date=April 2001 |pmid=11294827 |doi=10.1210/edrv.22.2.0422 |url=}}</ref> <ref name="pmid7691194">{{cite journal |vauthors=Ziltener HJ, Maines-Bandiera S, Schrader JW, Auersperg N |title=Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium |journal=Biol. Reprod. |volume=49 |issue=3 |pages=635–41 |date=September 1993 |pmid=7691194 |doi= |url=}}</ref><ref name="pmid8824555">{{cite journal |vauthors=Marth C, Zeimet AG, Herold M, Brumm C, Windbichler G, Müller-Holzner E, Offner F, Feichtinger H, Zwierzina H, Daxenbichler G |title=Different effects of interferons, interleukin-1beta and tumor necrosis factor-alpha in normal (OSE) and malignant human ovarian epithelial cells |journal=Int. J. Cancer |volume=67 |issue=6 |pages=826–30 |date=September 1996 |pmid=8824555 |doi=10.1002/(SICI)1097-0215(19960917)67:6<826::AID-IJC12>3.0.CO;2-# |url=}}</ref>
 |
 * Regulation of immune response
 * May increase vasculogenesis and survival
 |}
+=== The Origin of Neoplasia in Epithelial Ovarian Cancer: A Mystery to Solve ===
+* The previous proposition regarding the origin of epithelial ovarian cancers was that these tumors originated from surface epithelium of the ovaries and the neoplastic and metaplastic changes led to their differentiation into various histological subtypes such as serous tumors, clear cell carcinoma and endometrioid tumors.<ref name="pmid255566183">{{cite journal |vauthors=Devouassoux-Shisheboran M, Genestie C |title=Pathobiology of ovarian carcinomas |journal=Chin J Cancer |volume=34 |issue=1 |pages=50–5 |date=January 2015 |pmid=25556618 |pmc=4302089 |doi=10.5732/cjc.014.10273 |url=}}</ref><ref name="pmid6090303">{{cite journal |vauthors=Lauchlan SC |title=Metaplasias and neoplasias of Müllerian epithelium |journal=Histopathology |volume=8 |issue=4 |pages=543–57 |date=July 1984 |pmid=6090303 |doi= |url=}}</ref><ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref>
+* However the surface epithelium of ovaries is derived from mesothelium and ovarian carcinoma resembled more closely to tissues derived from Mullerian ducts rather than ovarian mesothelium derived surface epithelium. For example serous cancer histology resembles fallopian tube epithelium and that of transitional cells tumor resembles urinary bladder. Likewise endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis, and Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives.<ref name="pmid255566183">{{cite journal |vauthors=Devouassoux-Shisheboran M, Genestie C |title=Pathobiology of ovarian carcinomas |journal=Chin J Cancer |volume=34 |issue=1 |pages=50–5 |date=January 2015 |pmid=25556618 |pmc=4302089 |doi=10.5732/cjc.014.10273 |url=}}</ref><ref name="pmid6090303">{{cite journal |vauthors=Lauchlan SC |title=Metaplasias and neoplasias of Müllerian epithelium |journal=Histopathology |volume=8 |issue=4 |pages=543–57 |date=July 1984 |pmid=6090303 |doi= |url=}}</ref><ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid10366144">{{cite journal |vauthors=Riopel MA, Ronnett BM, Kurman RJ |title=Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas |journal=Am. J. Surg. Pathol. |volume=23 |issue=6 |pages=617–35 |date=June 1999 |pmid=10366144 |doi= |url=}}</ref>
+* Secondly the genetic profile also overcasts shadows of doubt about origin of these neoplasms from ovarian surface epithelium. The presence of identical TP53 mutations in serous tubal intra-epithelial tumors and ovarian serous tumors puts a question mark on ovarian origin theory. Gene expression profiling also demonstrated the presence of similarities between serous tubal intra-epithelial tumors and ovarian serous tumors. The various theories of origin of epithelial ovarian cancers have been discussed below.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid17255760">{{cite journal |vauthors=Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP |title=Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship |journal=Am. J. Surg. Pathol. |volume=31 |issue=2 |pages=161–9 |date=February 2007 |pmid=17255760 |doi=10.1097/01.pas.0000213335.40358.47 |url=}}</ref><ref name="pmid16144910">{{cite journal |vauthors=Marquez RT, Baggerly KA, Patterson AP, Liu J, Broaddus R, Frumovitz M, Atkinson EN, Smith DI, Hartmann L, Fishman D, Berchuck A, Whitaker R, Gershenson DM, Mills GB, Bast RC, Lu KH |title=Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon |journal=Clin. Cancer Res. |volume=11 |issue=17 |pages=6116–26 |date=September 2005 |pmid=16144910 |doi=10.1158/1078-0432.CCR-04-2509 |url=}}</ref>
+==== Ovarian Origin of Ovarian Epithelial Tumors ====
+* This simple theory states that ovarian epithelial tumors simply originate from surface epithelium of ovaries through various neoplastic changes. But recent data has highlighted the numerous inconsistencies in the theory that was once highly regarded as accurate.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref>
+* Firstly surface epithelium of ovaries is derived from mesothelium and ovarian carcinoma resembled more closely to tissues derived from Mullerian ducts rather than ovarian mesothelium derived surface epithelium. For example serous cancer histology resembles fallopian tube epithelium and that of transitional cells tumor resembles urinary bladder. Likewise endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis, and Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives.<ref name="pmid255566183">{{cite journal |vauthors=Devouassoux-Shisheboran M, Genestie C |title=Pathobiology of ovarian carcinomas |journal=Chin J Cancer |volume=34 |issue=1 |pages=50–5 |date=January 2015 |pmid=25556618 |pmc=4302089 |doi=10.5732/cjc.014.10273 |url=}}</ref><ref name="pmid6090303">{{cite journal |vauthors=Lauchlan SC |title=Metaplasias and neoplasias of Müllerian epithelium |journal=Histopathology |volume=8 |issue=4 |pages=543–57 |date=July 1984 |pmid=6090303 |doi= |url=}}</ref><ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid10366144">{{cite journal |vauthors=Riopel MA, Ronnett BM, Kurman RJ |title=Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas |journal=Am. J. Surg. Pathol. |volume=23 |issue=6 |pages=617–35 |date=June 1999 |pmid=10366144 |doi= |url=}}</ref>
+* Secondly the presence of identical TP53 mutations in serous tubal intra-epithelial tumors and ovarian serous tumors puts a question mark on ovarian origin theory. Gene expression profiling also demonstrated the presence of similarities between serous tubal intra-epithelial tumors and ovarian serous tumors.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid17255760">{{cite journal |vauthors=Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP |title=Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship |journal=Am. J. Surg. Pathol. |volume=31 |issue=2 |pages=161–9 |date=February 2007 |pmid=17255760 |doi=10.1097/01.pas.0000213335.40358.47 |url=}}</ref><ref name="pmid16144910">{{cite journal |vauthors=Marquez RT, Baggerly KA, Patterson AP, Liu J, Broaddus R, Frumovitz M, Atkinson EN, Smith DI, Hartmann L, Fishman D, Berchuck A, Whitaker R, Gershenson DM, Mills GB, Bast RC, Lu KH |title=Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon |journal=Clin. Cancer Res. |volume=11 |issue=17 |pages=6116–26 |date=September 2005 |pmid=16144910 |doi=10.1158/1078-0432.CCR-04-2509 |url=}}</ref>
+* The expression of PAX8 and absence of calretinin in high grade serous tumors presents another problem with theory of ovarian origin because PAX8 is a Müllerian marker and calretinin is a mesothelium marker.<ref
+* In cases when fallopian tubes were removed carefully along with ovarian and/or peritoneal serous cancer, the involvement of mucosa of the tubes were found to be involved in about 70% of the cases.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref>
+* In 2001, a Dutch study revealed the presence of high grade serous carcinomas in fallopian tubes of women with genetic susceptibility to hereditary ovarian cancers with no evidence of such lesions in ovaries of same women. These lesions were termed as serous tubal intra-epithelial tumors.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid17761984">{{cite journal |vauthors=Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, Feltmate CM, Berkowitz RS, Muto MG |title=Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3985–90 |date=September 2007 |pmid=17761984 |doi=10.1200/JCO.2007.12.2622 |url=}}</ref><ref name="pmid17255760">{{cite journal |vauthors=Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP |title=Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship |journal=Am. J. Surg. Pathol. |volume=31 |issue=2 |pages=161–9 |date=February 2007 |pmid=17255760 |doi=10.1097/01.pas.0000213335.40358.47 |url=}}</ref><ref name="pmid11745677">{{cite journal |vauthors=Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, Verheijen RH |title=Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer |journal=J. Pathol. |volume=195 |issue=4 |pages=451–6 |date=November 2001 |pmid=11745677 |doi=10.1002/path.1000 |url=}}</ref>
+* Additional studies demonstrated the presence of similar lesions in fallopian tubes of women without genetic susceptibility to ovarian cancer. In cases when fallopian tubes were removed carefully along with ovarian and/or peritoneal serous cancer, the involvement of mucosa of the tubes were found to be involved in about 70% of the cases.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid17761984">{{cite journal |vauthors=Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, Feltmate CM, Berkowitz RS, Muto MG |title=Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3985–90 |date=September 2007 |pmid=17761984 |doi=10.1200/JCO.2007.12.2622 |url=}}</ref><ref name="pmid17255760">{{cite journal |vauthors=Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP |title=Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship |journal=Am. J. Surg. Pathol. |volume=31 |issue=2 |pages=161–9 |date=February 2007 |pmid=17255760 |doi=10.1097/01.pas.0000213335.40358.47 |url=}}</ref><ref name="pmid11745677">{{cite journal |vauthors=Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, Verheijen RH |title=Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer |journal=J. Pathol. |volume=195 |issue=4 |pages=451–6 |date=November 2001 |pmid=11745677 |doi=10.1002/path.1000 |url=}}</ref>
+* In an attempt to explain these apparent discrepancies it was postulated that invagination of ovarian epithelium into ovarian stroma creates '''“cortical inclusion cysts”'''. These cysts then undergo various metaplastic changes ('''coelomic metaplasia hypothesis''') due to hormonal influence and repair mechanisms to give rise to ovarian epithelial cancer. Although these cysts are present but no such neoplastic and metaplastic transformation has been reported or observed until now. Additionally the observed cysts could dimply be the transplants from the fallopian tubes.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid20436685">{{cite journal |vauthors=Pothuri B, Leitao MM, Levine DA, Viale A, Olshen AB, Arroyo C, Bogomolniy F, Olvera N, Lin O, Soslow RA, Robson ME, Offit K, Barakat RR, Boyd J |title=Genetic analysis of the early natural history of epithelial ovarian carcinoma |journal=PLoS ONE |volume=5 |issue=4 |pages=e10358 |date=April 2010 |pmid=20436685 |pmc=2859950 |doi=10.1371/journal.pone.0010358 |url=}}</ref>
+* Another proposed theory is the implantation of tubal epithelium from fimbria into ovarian inclusion cysts due to their close contact during the ovulation process. This may explain the origin of serous tumor of the ovaries but unable to explain other tumor sub-types.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref>
+==== Secondary Müllerian System ====
+* This theory tries to explain this apparent enigma of existence of Müllerian epithelial lesions in locations not derived from Müllerian ducts such as ovaries and peritoneal cavity. Secondary Müllerian system consists of müllerian-type tissue lined cysts that are located in close proximity to the ovaries.<ref name="pmid25556618">{{cite journal |vauthors=Devouassoux-Shisheboran M, Genestie C |title=Pathobiology of ovarian carcinomas |journal=Chin J Cancer |volume=34 |issue=1 |pages=50–5 |date=January 2015 |pmid=25556618 |pmc=4302089 |doi=10.5732/cjc.014.10273 |url=}}</ref><ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref>
+* According to this hypothesis Müllerian tissues, considered by some as vestigial, are found in locations such as para-tubal and para-ovarian locations and these tissues or cysts, not the ovarian epithelium itself, give rise to epithelial ovarian neoplasms. These tumors, arising outside ovaries, then enlarge and become implants/or compress ovaries and present as ovarian tumors.<ref name="pmid255566183">{{cite journal |vauthors=Devouassoux-Shisheboran M, Genestie C |title=Pathobiology of ovarian carcinomas |journal=Chin J Cancer |volume=34 |issue=1 |pages=50–5 |date=January 2015 |pmid=25556618 |pmc=4302089 |doi=10.5732/cjc.014.10273 |url=}}</ref><ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref>
+* But there are number of problems this theory fails to explain. For example mucinous epithelial tumors of ovaries resemble intestinal epithelium rather than endocervical epithelium. Also transitional cell tumor resemble morphologically to bladder epithelium that is not a derivative of Müllerian system.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid10366144">{{cite journal |vauthors=Riopel MA, Ronnett BM, Kurman RJ |title=Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas |journal=Am. J. Surg. Pathol. |volume=23 |issue=6 |pages=617–35 |date=June 1999 |pmid=10366144 |doi= |url=}}</ref>
+* Another apparent flaw is that transition of these cysts lined by Müllerian-type epithelium, although present, to carcinoma has been very rare.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref>
+==== The Origin of Epithelial Ovarian Tumors from Fallopian Tubes and Endometrium ====
+* The evidence from recent studies indicate that majority of epithelial ovarian cancers have their origin outside ovaries, especially from fallopian tubes and endometrium. This idea is supported by several observations in a number of studies.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref>
+* The histology of serous, endometrioid and clear cell carcinoma demonstrates that their morphology is similar to that fallopian tubes, and endometrium rather than ovarian epithelium.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid19342944">{{cite journal |vauthors=Veras E, Mao TL, Ayhan A, Ueda S, Lai H, Hayran M, Shih IeM, Kurman RJ |title=Cystic and adenofibromatous clear cell carcinomas of the ovary: distinctive tumors that differ in their pathogenesis and behavior: a clinicopathologic analysis of 122 cases |journal=Am. J. Surg. Pathol. |volume=33 |issue=6 |pages=844–53 |date=June 2009 |pmid=19342944 |doi=10.1097/PAS.0b013e31819c4271 |url=}}</ref><ref name="pmid9383841">{{cite journal |vauthors=Martin DC |title=Cancer and endometriosis: do we need to be concerned? |journal=Semin. Reprod. Endocrinol. |volume=15 |issue=3 |pages=319–24 |date=1997 |pmid=9383841 |doi=10.1055/s-2008-1068762 |url=}}</ref>
+* Presence of PAX8, a Müllerian marker, and absence of calretinin, a mestothelial marker, further supports the theory. Moreover the genetic profile expression similarities and presence of similar TP53 mutation signatures in serous tubal intra-epithelial tumors and epithelial ovarian cancers also supports the extra-ovarian origin of epithelial ovarian cancer.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid17255760">{{cite journal |vauthors=Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP |title=Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship |journal=Am. J. Surg. Pathol. |volume=31 |issue=2 |pages=161–9 |date=February 2007 |pmid=17255760 |doi=10.1097/01.pas.0000213335.40358.47 |url=}}</ref><ref name="pmid16144910">{{cite journal |vauthors=Marquez RT, Baggerly KA, Patterson AP, Liu J, Broaddus R, Frumovitz M, Atkinson EN, Smith DI, Hartmann L, Fishman D, Berchuck A, Whitaker R, Gershenson DM, Mills GB, Bast RC, Lu KH |title=Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon |journal=Clin. Cancer Res. |volume=11 |issue=17 |pages=6116–26 |date=September 2005 |pmid=16144910 |doi=10.1158/1078-0432.CCR-04-2509 |url=}}</ref>.
+* In 2001, a Dutch study revealed the presence of high grade serous carcinomas in fallopian tubes of women with genetic susceptibility to hereditary ovarian cancers with no evidence of such lesions in ovaries of same women. These lesions were termed as serous tubal intra-epithelial tumors.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid17255760">{{cite journal |vauthors=Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP |title=Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship |journal=Am. J. Surg. Pathol. |volume=31 |issue=2 |pages=161–9 |date=February 2007 |pmid=17255760 |doi=10.1097/01.pas.0000213335.40358.47 |url=}}</ref><ref name="pmid11745677">{{cite journal |vauthors=Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, Verheijen RH |title=Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer |journal=J. Pathol. |volume=195 |issue=4 |pages=451–6 |date=November 2001 |pmid=11745677 |doi=10.1002/path.1000 |url=}}</ref><ref name="pmid17761984">{{cite journal |vauthors=Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, Feltmate CM, Berkowitz RS, Muto MG |title=Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3985–90 |date=September 2007 |pmid=17761984 |doi=10.1200/JCO.2007.12.2622 |url=}}</ref>
+* Additional studies demonstrated the presence of similar lesions in fallopian tubes of women without genetic susceptibility to ovarian cancer. In cases when fallopian tubes were removed carefully along with ovarian and/or peritoneal serous cancer, the involvement of mucosa of the tubes were found to be involved in about 70% of the cases.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid17255760">{{cite journal |vauthors=Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP |title=Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship |journal=Am. J. Surg. Pathol. |volume=31 |issue=2 |pages=161–9 |date=February 2007 |pmid=17255760 |doi=10.1097/01.pas.0000213335.40358.47 |url=}}</ref><ref name="pmid11745677">{{cite journal |vauthors=Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, Verheijen RH |title=Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer |journal=J. Pathol. |volume=195 |issue=4 |pages=451–6 |date=November 2001 |pmid=11745677 |doi=10.1002/path.1000 |url=}}</ref><ref name="pmid17761984">{{cite journal |vauthors=Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, Feltmate CM, Berkowitz RS, Muto MG |title=Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3985–90 |date=September 2007 |pmid=17761984 |doi=10.1200/JCO.2007.12.2622 |url=}}</ref>
+* These tubal serous lesions were located in fimbria in almost all of the cases, giving rise to the proposition that serous tumors originated in fallopian tubes and then implantation into ovaries.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid12893227">{{cite journal |vauthors=Piek JM, Verheijen RH, Kenemans P, Massuger LF, Bulten H, van Diest PJ |title=BRCA1/2-related ovarian cancers are of tubal origin: a hypothesis |journal=Gynecol. Oncol. |volume=90 |issue=2 |pages=491 |date=August 2003 |pmid=12893227 |doi= |url=}}</ref><ref name="pmid17255760">{{cite journal |vauthors=Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP |title=Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship |journal=Am. J. Surg. Pathol. |volume=31 |issue=2 |pages=161–9 |date=February 2007 |pmid=17255760 |doi=10.1097/01.pas.0000213335.40358.47 |url=}}</ref><ref name="pmid16434898">{{cite journal |vauthors=Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, Garber JE, Cramer DW, Crum CP |title=The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome |journal=Am. J. Surg. Pathol. |volume=30 |issue=2 |pages=230–6 |date=February 2006 |pmid=16434898 |doi= |url=}}</ref>
+* The association between adnexal malignant mixed mesodermal tumors and serous tubal intraepithelial tumors pints further in direction of tubal origin of these epithelial ovarian tumors.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid24328014">{{cite journal |vauthors=Lee TY, Lee C, Choi WJ, Lee JY, Kim HY |title=Synchronous occurrence of primary malignant mixed müllerian tumor in ovary and uterus |journal=Obstet Gynecol Sci |volume=56 |issue=4 |pages=269–72 |date=July 2013 |pmid=24328014 |pmc=3784138 |doi=10.5468/ogs.2013.56.4.269 |url=}}</ref><ref name="pmid28469326">{{cite journal |vauthors=Gupta AJ, Singh M, Rani P, Jain S, Khurana N, Sahu L |title=Malignant mixed mullerian tumor of ovary-scrape cytology: Findings with review of literature |journal=J Cytol |volume=34 |issue=2 |pages=125–126 |date=2017 |pmid=28469326 |pmc=5398022 |doi=10.4103/0970-9371.203568 |url=}}</ref>
+* Similarly morphologic and molecular studies have indicated that endometrioid and clear cell carcinoma of the ovaries have their origin in endometriosis. These studies suggest that these tumors arise from endometriomas, the endometriotic cysts that are present outside the normal endometrium.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid19342944">{{cite journal |vauthors=Veras E, Mao TL, Ayhan A, Ueda S, Lai H, Hayran M, Shih IeM, Kurman RJ |title=Cystic and adenofibromatous clear cell carcinomas of the ovary: distinctive tumors that differ in their pathogenesis and behavior: a clinicopathologic analysis of 122 cases |journal=Am. J. Surg. Pathol. |volume=33 |issue=6 |pages=844–53 |date=June 2009 |pmid=19342944 |doi=10.1097/PAS.0b013e31819c4271 |url=}}</ref><ref name="pmid9383841">{{cite journal |vauthors=Martin DC |title=Cancer and endometriosis: do we need to be concerned? |journal=Semin. Reprod. Endocrinol. |volume=15 |issue=3 |pages=319–24 |date=1997 |pmid=9383841 |doi=10.1055/s-2008-1068762 |url=}}</ref>
+* This theory regarding the origin of endometrioid and clear cell carcinoma of the ovary is supported by the fact that tubal ligation that prevents endometriotic implants into ovary and peritoneum in endometriosis has a protective effect on endometrioid and clear cell type cancers but not on the serous cancer of the ovary because it doesn't occlude the connection between fimbria and the ovaries.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid11570411">{{cite journal |vauthors=Piek JM, van Diest PJ, Zweemer RP, Kenemans P, Verheijen RH |title=Tubal ligation and risk of ovarian cancer |journal=Lancet |volume=358 |issue=9284 |pages=844 |date=September 2001 |pmid=11570411 |doi=10.1016/S0140-6736(01)05992-X |url=}}</ref><ref name="pmid8922304">{{cite journal |vauthors=Rosenblatt KA, Thomas DB |title=Reduced risk of ovarian cancer in women with a tubal ligation or hysterectomy. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives |journal=Cancer Epidemiol. Biomarkers Prev. |volume=5 |issue=11 |pages=933–5 |date=November 1996 |pmid=8922304 |doi= |url=}}</ref>
+==== The Origin of Mucinous Tumors of Gastrointestinal Type and Transitional Cell (Brenner) Tumors: Still a Mystery to Solve ====
+* Mucinous and the transitional tumors of ovaries are two of the least common types of the epithelial ovarian tumors. In fact, most of the mucinous tumors in ovaries are secondary and primary tumors only form about 3% of all epithelial ovarian cancers. Mucinous epithelium in mucinous tumors of ovaries resemble more to intestinal mucinous epithelium rather than that of endocervix as was previously argued. Transitional cell tumors, on the other hand, are closer to bladder epithelium in histological studies.<ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid10366144">{{cite journal |vauthors=Riopel MA, Ronnett BM, Kurman RJ |title=Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas |journal=Am. J. Surg. Pathol. |volume=23 |issue=6 |pages=617–35 |date=June 1999 |pmid=10366144 |doi= |url=}}</ref><ref name="pmid17527072">{{cite journal |vauthors=Vang R, Gown AM, Zhao C, Barry TS, Isacson C, Richardson MS, Ronnett BM |title=Ovarian mucinous tumors associated with mature cystic teratomas: morphologic and immunohistochemical analysis identifies a subset of potential teratomatous origin that shares features of lower gastrointestinal tract mucinous tumors more commonly encountered as secondary tumors in the ovary |journal=Am. J. Surg. Pathol. |volume=31 |issue=6 |pages=854–69 |date=June 2007 |pmid=17527072 |doi=10.1097/PAS.0b013e31802efb45 |url=}}</ref><ref name="pmid18976011">{{cite journal |vauthors=Seidman JD, Khedmati F |title=Exploring the histogenesis of ovarian mucinous and transitional cell (Brenner) neoplasms and their relationship with Walthard cell nests: a study of 120 tumors |journal=Arch. Pathol. Lab. Med. |volume=132 |issue=11 |pages=1753–60 |date=November 2008 |pmid=18976011 |doi=10.1043/1543-2165-132.11.1753 |url=}}</ref>
+* Another study demonstrated the presence of Brenner tumor foci in mucinous cystadenoma in almost one fifth of the cases. Alternatively the association of mucinous tumors with Walthard cell nests, which are composed of transitional-type epithelium, also indicates the connection between mucinous and transitional tumors.<ref name="pmid18317228">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications |journal=Int. J. Gynecol. Pathol. |volume=27 |issue=2 |pages=151–60 |date=April 2008 |pmid=18317228 |pmc=2794425 |doi=10.1097/PGP.0b013e318161e4f5 |url=}}</ref><ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid19038766">{{cite journal |vauthors=Dubeau L |title=The cell of origin of ovarian epithelial tumours |journal=Lancet Oncol. |volume=9 |issue=12 |pages=1191–7 |date=December 2008 |pmid=19038766 |pmc=4176875 |doi=10.1016/S1470-2045(08)70308-5 |url=}}</ref><ref name="pmid17527072">{{cite journal |vauthors=Vang R, Gown AM, Zhao C, Barry TS, Isacson C, Richardson MS, Ronnett BM |title=Ovarian mucinous tumors associated with mature cystic teratomas: morphologic and immunohistochemical analysis identifies a subset of potential teratomatous origin that shares features of lower gastrointestinal tract mucinous tumors more commonly encountered as secondary tumors in the ovary |journal=Am. J. Surg. Pathol. |volume=31 |issue=6 |pages=854–69 |date=June 2007 |pmid=17527072 |doi=10.1097/PAS.0b013e31802efb45 |url=}}</ref><ref name="pmid18976011">{{cite journal |vauthors=Seidman JD, Khedmati F |title=Exploring the histogenesis of ovarian mucinous and transitional cell (Brenner) neoplasms and their relationship with Walthard cell nests: a study of 120 tumors |journal=Arch. Pathol. Lab. Med. |volume=132 |issue=11 |pages=1753–60 |date=November 2008 |pmid=18976011 |doi=10.1043/1543-2165-132.11.1753 |url=}}</ref>
+== Pathogenesis ==
+[[File:DNA damage and repair mechanisms..jpg|alt=DNA damage and repair mechanisms.|center|frame|DNA damage and repair mechanisms.<ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref>]]
+=== Secondary Müllerian System ===
+* Although ovarian surface epithelium is not a derivative of Müllerian ducts but ovarian epithelial cancers are characterized by presence of Müllerian lesions.<ref name="pmid25556618">{{cite journal |vauthors=Devouassoux-Shisheboran M, Genestie C |title=Pathobiology of ovarian carcinomas |journal=Chin J Cancer |volume=34 |issue=1 |pages=50–5 |date=January 2015 |pmid=25556618 |pmc=4302089 |doi=10.5732/cjc.014.10273 |url=}}</ref>
+* Serous carcinoma of ovary is though to originate from fallopian tubes while clear cell, endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis. Similarly Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives..<ref name="pmid255566183">{{cite journal |vauthors=Devouassoux-Shisheboran M, Genestie C |title=Pathobiology of ovarian carcinomas |journal=Chin J Cancer |volume=34 |issue=1 |pages=50–5 |date=January 2015 |pmid=25556618 |pmc=4302089 |doi=10.5732/cjc.014.10273 |url=}}</ref><ref name="pmid6090303">{{cite journal |vauthors=Lauchlan SC |title=Metaplasias and neoplasias of Müllerian epithelium |journal=Histopathology |volume=8 |issue=4 |pages=543–57 |date=July 1984 |pmid=6090303 |doi= |url=}}</ref>
+* Secondary Müllerian system is a hypothesis that tries to explain this apparent enigma of existence of Müllerian epithelial lesions in locations not derived from Müllerian ducts such as ovaries and peritoneal cavity.<ref name="pmid255566182">{{cite journal |vauthors=Devouassoux-Shisheboran M, Genestie C |title=Pathobiology of ovarian carcinomas |journal=Chin J Cancer |volume=34 |issue=1 |pages=50–5 |date=January 2015 |pmid=25556618 |pmc=4302089 |doi=10.5732/cjc.014.10273 |url=}}</ref><ref name="pmid6090303">{{cite journal |vauthors=Lauchlan SC |title=Metaplasias and neoplasias of Müllerian epithelium |journal=Histopathology |volume=8 |issue=4 |pages=543–57 |date=July 1984 |pmid=6090303 |doi= |url=}}</ref>
+* According to this hypothesis, Müllerian tissues, considered as vestigial, are found in locations such as para-tubal and para-ovarian locations and these tissues or cysts, not the ovarian epithelium itself, give rise to epithelial ovarian neoplasms.<ref name="pmid255566183">{{cite journal |vauthors=Devouassoux-Shisheboran M, Genestie C |title=Pathobiology of ovarian carcinomas |journal=Chin J Cancer |volume=34 |issue=1 |pages=50–5 |date=January 2015 |pmid=25556618 |pmc=4302089 |doi=10.5732/cjc.014.10273 |url=}}</ref><ref name="pmid6090303">{{cite journal |vauthors=Lauchlan SC |title=Metaplasias and neoplasias of Müllerian epithelium |journal=Histopathology |volume=8 |issue=4 |pages=543–57 |date=July 1984 |pmid=6090303 |doi= |url=}}</ref>
+=== Hereditary Ovarian Carcinoma: An Understanding of Genome ===
+* More than one fifth cases of ovarian epithelial cancers are found to have hereditary causes. These hereditary diseases/syndromes appear to possess heterogeneous, both in genetic anomalies and in clinical manifestations.<ref name="pmid19383374">{{cite journal |vauthors=Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK |title=Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management |journal=Mol Oncol |volume=3 |issue=2 |pages=97–137 |date=April 2009 |pmid=19383374 |doi=10.1016/j.molonc.2009.02.004 |url=}}</ref><ref name="pmid28794804">{{cite journal |vauthors=Neff RT, Senter L, Salani R |title=BRCA mutation in ovarian cancer: testing, implications and treatment considerations |journal=Ther Adv Med Oncol |volume=9 |issue=8 |pages=519–531 |date=August 2017 |pmid=28794804 |doi=10.1177/1758834017714993 |url=}}</ref>
+* Majority of these hereditary cancers are caused by two genetic anomalies: a defect in so-called mismatch repair genes named as MLH1, MSH2, MSH6 and PMS2, and in DNA defects repair genes named as BRCA1 and BRCA2.<ref name="pmid19383374">{{cite journal |vauthors=Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK |title=Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management |journal=Mol Oncol |volume=3 |issue=2 |pages=97–137 |date=April 2009 |pmid=19383374 |doi=10.1016/j.molonc.2009.02.004 |url=}}</ref><ref name="pmid28794804">{{cite journal |vauthors=Neff RT, Senter L, Salani R |title=BRCA mutation in ovarian cancer: testing, implications and treatment considerations |journal=Ther Adv Med Oncol |volume=9 |issue=8 |pages=519–531 |date=August 2017 |pmid=28794804 |doi=10.1177/1758834017714993 |url=}}</ref><ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid23572416">{{cite journal |vauthors=Martín-López JV, Fishel R |title=The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome |journal=Fam. Cancer |volume=12 |issue=2 |pages=159–68 |date=June 2013 |pmid=23572416 |pmc=4235668 |doi=10.1007/s10689-013-9635-x |url=}}</ref>
+==== The Role of BRCA1 Gene in DNA Repair ====
+* BRCA1 is a protein that, through a complex interaction with other proteins such as tumor suppressors, regulators of cell cycle and other DNA repair genes, is involved in DNA repair pathways.<ref name="pmid19383374">{{cite journal |vauthors=Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK |title=Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management |journal=Mol Oncol |volume=3 |issue=2 |pages=97–137 |date=April 2009 |pmid=19383374 |doi=10.1016/j.molonc.2009.02.004 |url=}}</ref><ref name="pmid28794804">{{cite journal |vauthors=Neff RT, Senter L, Salani R |title=BRCA mutation in ovarian cancer: testing, implications and treatment considerations |journal=Ther Adv Med Oncol |volume=9 |issue=8 |pages=519–531 |date=August 2017 |pmid=28794804 |doi=10.1177/1758834017714993 |url=}}</ref> <ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+* This protein has two domains: amino-terminal RING domain and a BRCT domain. The former posses E3 ubiquitin ligase activity and the later facilitates phospho-protein binding.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+* Tumor suppressor role of both domains is highlighted by the fact that mutations in both domains have been found in breast and gynecological malignancies.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+* The major role of BRCA1 appears to sense and repair double stranded DNA breaks in homologous recombination.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+'''Binding of BRCA1 to double stranded DNA breaks through its association with the abraxas–RAP80 macro-complex → processing of double stranded DNA breaks through interaction of BRCA1 with CtIP (transcription factor) and the MRN complex → The BRCA1–CtIP complex → CtIP-mediated 5′-end resection of double stranded DNA breaks'''
+* Another role of BRCA1 in Non-homologous end joining ('''NHEJ''') pathway has also been proposed. Though still controversial, it has been suggested that BRCA1 plays a critical function by removal of Non-homologous end joining proteins such as p53-binding protein 1 (53BP1) from double stranded DNA breaks.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+* G1/S, S-phase and G2/M checkpoints activation during cell cycle has also been found defective in cells lacking or having mutated BRCA1. A brief interaction of BRCA1 with cell cycle is given below:<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+'''Phosphorylation of BRCA1 by ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related protein (ATR) → phosphorylation of p53 → transcriptional induction of the cyclin dependent kinase (CDK) inhibitor p21.'''
+[[File:A summary of BRCA1 activity and function in DNA damage repair.png|center|frame|<ref name="pmid181796933">{{cite journal |vauthors=Wu W, Koike A, Takeshita T, Ohta T |title=The ubiquitin E3 ligase activity of BRCA1 and its biological functions |journal=Cell Div |volume=3 |issue= |pages=1 |date=January 2008 |pmid=18179693 |pmc=2254412 |doi=10.1186/1747-1028-3-1 |url=}}</ref>'''<big>A summary of BRCA1 activity and function in DNA damage repair</big>''']]
+==== The Role of BRCA2 Gene in DNA Repair ====
+* BRCA2, as opposed to BRCA1 that functions in multiple pathways involving DNA repair, has its primary role in homologous recombination (HR).<ref name="pmid19383374">{{cite journal |vauthors=Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK |title=Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management |journal=Mol Oncol |volume=3 |issue=2 |pages=97–137 |date=April 2009 |pmid=19383374 |doi=10.1016/j.molonc.2009.02.004 |url=}}</ref><ref name="pmid28794804">{{cite journal |vauthors=Neff RT, Senter L, Salani R |title=BRCA mutation in ovarian cancer: testing, implications and treatment considerations |journal=Ther Adv Med Oncol |volume=9 |issue=8 |pages=519–531 |date=August 2017 |pmid=28794804 |doi=10.1177/1758834017714993 |url=}}</ref><ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+* DNA-binding domain (DBD) of BRCA2 binds single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) and eight BRC repeats. The eight BRC repeats bind RAD51 (a recombinase).<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid20729858">{{cite journal |vauthors=Thorslund T, McIlwraith MJ, Compton SA, Lekomtsev S, Petronczki M, Griffith JD, West SC |title=The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA |journal=Nat. Struct. Mol. Biol. |volume=17 |issue=10 |pages=1263–5 |date=October 2010 |pmid=20729858 |pmc=4041013 |doi=10.1038/nsmb.1905 |url=}}</ref>
+* The binding of BRCA2 to RAD51 leads to recruitment of RAD51 to double stranded DNA breaks, an essential step in homologous recombination double stranded DNA repair.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid20729858">{{cite journal |vauthors=Thorslund T, McIlwraith MJ, Compton SA, Lekomtsev S, Petronczki M, Griffith JD, West SC |title=The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA |journal=Nat. Struct. Mol. Biol. |volume=17 |issue=10 |pages=1263–5 |date=October 2010 |pmid=20729858 |pmc=4041013 |doi=10.1038/nsmb.1905 |url=}}</ref><ref name="pmid19303847">{{cite journal |vauthors=Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK, Venkitaraman AR, Kowalczykowski SC |title=The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51 |journal=Cell |volume=136 |issue=6 |pages=1032–43 |date=March 2009 |pmid=19303847 |pmc=2669112 |doi=10.1016/j.cell.2009.02.019 |url=}}</ref>
+* After recruitment, BRCA2 helps RAD51 in displacement of replication protein A (RPA) in single stranded DNA. It then prevents nucleation of RAD51 at double stranded DNA and promotes RAD51 filament formation on single stranded DNA.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid19303847">{{cite journal |vauthors=Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK, Venkitaraman AR, Kowalczykowski SC |title=The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51 |journal=Cell |volume=136 |issue=6 |pages=1032–43 |date=March 2009 |pmid=19303847 |pmc=2669112 |doi=10.1016/j.cell.2009.02.019 |url=}}</ref>
+==== The Connection Between BRCA1 and BRCA2 ====
+* The common pathway that seems to link both BRCA! and BRCA2 proteins is homologous recombination mediated repair.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid19369211">{{cite journal |vauthors=Sy SM, Huen MS, Chen J |title=PALB2 is an integral component of the BRCA complex required for homologous recombination repair |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=106 |issue=17 |pages=7155–60 |date=April 2009 |pmid=19369211 |pmc=2678481 |doi=10.1073/pnas.0811159106 |url=}}</ref><ref name="pmid16793542">{{cite journal |vauthors=Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM |title=Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2 |journal=Mol. Cell |volume=22 |issue=6 |pages=719–29 |date=June 2006 |pmid=16793542 |doi=10.1016/j.molcel.2006.05.022 |url=}}</ref>
+* Partner and localizer of BRCA2 (PALB2) physically connects BRCA1 and BRCA2 through N-terminal coiled-coil domain and the C terminus.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid19369211">{{cite journal |vauthors=Sy SM, Huen MS, Chen J |title=PALB2 is an integral component of the BRCA complex required for homologous recombination repair |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=106 |issue=17 |pages=7155–60 |date=April 2009 |pmid=19369211 |pmc=2678481 |doi=10.1073/pnas.0811159106 |url=}}</ref><ref name="pmid16793542">{{cite journal |vauthors=Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM |title=Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2 |journal=Mol. Cell |volume=22 |issue=6 |pages=719–29 |date=June 2006 |pmid=16793542 |doi=10.1016/j.molcel.2006.05.022 |url=}}</ref>
+* The interaction between BRCA2 and PALB2 is observed for two critical function in homologous recombination mediated repair: interaction of RAD51 with replication protein A (RPA) in single stranded DNA and recruitment of BRCA2 and RAD51 on the site of DNA damage.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+==== The Role of Mismatch Repair Genes ====
+* Mismatch repair genes mutated in pathogenesis of hereditary epithelial ovarian cancer include human MutS homolog (MSH2 and 6), the human MutL homolog (''MLH1 and 3''), and ''p''ost-''meiotic s''egregation MutL homolog (''PMS2'') genes.<ref name="pmid19383374">{{cite journal |vauthors=Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK |title=Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management |journal=Mol Oncol |volume=3 |issue=2 |pages=97–137 |date=April 2009 |pmid=19383374 |doi=10.1016/j.molonc.2009.02.004 |url=}}</ref><ref name="pmid28794804">{{cite journal |vauthors=Neff RT, Senter L, Salani R |title=BRCA mutation in ovarian cancer: testing, implications and treatment considerations |journal=Ther Adv Med Oncol |volume=9 |issue=8 |pages=519–531 |date=August 2017 |pmid=28794804 |doi=10.1177/1758834017714993 |url=}}</ref><ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid23572416">{{cite journal |vauthors=Martín-López JV, Fishel R |title=The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome |journal=Fam. Cancer |volume=12 |issue=2 |pages=159–68 |date=June 2013 |pmid=23572416 |pmc=4235668 |doi=10.1007/s10689-013-9635-x |url=}}</ref>
+* A simplified version of repair mechanism by mismatch repair genes products is described below:<ref name="pmid23572416">{{cite journal |vauthors=Martín-López JV, Fishel R |title=The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome |journal=Fam. Cancer |volume=12 |issue=2 |pages=159–68 |date=June 2013 |pmid=23572416 |pmc=4235668 |doi=10.1007/s10689-013-9635-x |url=}}</ref><ref name="pmid18406444">{{cite journal |vauthors=Hsieh P, Yamane K |title=DNA mismatch repair: molecular mechanism, cancer, and ageing |journal=Mech. Ageing Dev. |volume=129 |issue=7-8 |pages=391–407 |date=2008 |pmid=18406444 |pmc=2574955 |doi=10.1016/j.mad.2008.02.012 |url=}}</ref>
+'''MutS homologs (MSHs) recognize the DNA mismatch → MutS homologs (MSHs) recruit MutL homologs (''MLHs)'' → excision of mismatched DNA → DNA polymerase re-synthesizes DNA.'''
+* Cells deficient in mismatch repair mechanism develop high rate of mutations including DNA sequences that include microsatellite repeats, resulting in microsatellite instability. This microsatellite instability has been implicated in impaired or defective signaling transduction, DNA repair and apoptosis, transcriptional regulation and protein translocation, and immune regulation.<ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid23572416">{{cite journal |vauthors=Martín-López JV, Fishel R |title=The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome |journal=Fam. Cancer |volume=12 |issue=2 |pages=159–68 |date=June 2013 |pmid=23572416 |pmc=4235668 |doi=10.1007/s10689-013-9635-x |url=}}</ref><ref name="pmid18406444">{{cite journal |vauthors=Hsieh P, Yamane K |title=DNA mismatch repair: molecular mechanism, cancer, and ageing |journal=Mech. Ageing Dev. |volume=129 |issue=7-8 |pages=391–407 |date=2008 |pmid=18406444 |pmc=2574955 |doi=10.1016/j.mad.2008.02.012 |url=}}</ref>
+[[File:Mismatch repair genes and oncogenesis..png|alt=Mismatch repair genes and oncogenesis.|center|frame|Mismatch repair genes and oncogenesis. [https://doi.org/10.3389/fonc.2012.00058 Source: Courtesy of G. Multoff and J. Radons, Frontiers in oncology]]]
+==== TP53 Mutations and Loss of Tumor Suppression ====
+* TP53 is a tumor suppressor gene that encodes for a transcription factor. The transcription factor encoded by TP53, known as p53, is a major regulator of cell cycle.<ref name="pmid260752292">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid28191499">{{cite journal |vauthors=Miller M, Shirole N, Tian R, Pal D, Sordella R |title=The Evolution of TP53 Mutations: From Loss-of-Function to Separation-of-Function Mutants |journal=J Cancer Biol Res |volume=4 |issue=4 |pages= |date=2016 |pmid=28191499 |pmc=5298884 |doi= |url=}}</ref>
+* Called by some as “Guardian of the Genome”, it is involved in variety of cellular functions such as cellular proliferation and cell cycle, apoptosis, and stability & integrity of the genome.<ref name="pmid260752293">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid28191499">{{cite journal |vauthors=Miller M, Shirole N, Tian R, Pal D, Sordella R |title=The Evolution of TP53 Mutations: From Loss-of-Function to Separation-of-Function Mutants |journal=J Cancer Biol Res |volume=4 |issue=4 |pages= |date=2016 |pmid=28191499 |pmc=5298884 |doi= |url=}}</ref>
+[[File:Downstream effect of p53 mutation..jpg|alt=Downstream effect of p53 mutation|center|frame|Downstream effect of p53 mutation.<ref name="pmid26082798">{{cite journal |vauthors=Pantziarka P |title=Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche |journal=Ecancermedicalscience |volume=9 |issue= |pages=541 |date=2015 |pmid=26082798 |pmc=4462886 |doi=10.3332/ecancer.2015.541 |url=}}</ref>]]
+{{Epithelial ovarian cancer}}
+=== An Insight Into The Molecular Pathogenesis of Epithelial Ovarian Cancer ===
+[[File:Genes.png|alt=Genetic alterations in cell cycle genes in epithelial ovarian cancer types.|center|frame|'''<big>Genetic alterations in cell cycle genes in epithelial ovarian cancer types.<ref name="pmid18665245">{{cite journal |vauthors=D'Andrilli G, Giordano A, Bovicelli A |title=Epithelial ovarian cancer: the role of cell cycle genes in the different histotypes |journal=Open Clin Cancer J |volume=2 |issue= |pages=7–12 |date=February 2008 |pmid=18665245 |pmc=2490600 |doi=10.2174/1874189400802010007 |url=}}</ref></big>'''|link=https://www.wikidoc.org/index.php/File:Genes.png]]
+==== Dualistic Model ====
+* This model attempts to explain clinicopathological and molecular genetic features of epithelial tumors by diving them in two subgroups: type I and type II epithelial ovarian tumors.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid15111296">{{cite journal |vauthors=Shih IeM, Kurman RJ |title=Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis |journal=Am. J. Pathol. |volume=164 |issue=5 |pages=1511–8 |date=May 2004 |pmid=15111296 |doi= |url=}}</ref>
+* Another advantage of this classification is that it tries to group precursor lesions with their putative malignant lesions.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid15111296">{{cite journal |vauthors=Shih IeM, Kurman RJ |title=Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis |journal=Am. J. Pathol. |volume=164 |issue=5 |pages=1511–8 |date=May 2004 |pmid=15111296 |doi= |url=}}</ref>
+* '''Type I''' tumors generally arise from endometriosis or fallopian tubal related serous epithelium. They are clinically stable, exhibit less aggressive clinical course and a different genetic than that of '''Type II.'''<ref name="pmid27983698">{{cite journal |vauthors=Rojas V, Hirshfield KM, Ganesan S, Rodriguez-Rodriguez L |title=Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment |journal=Int J Mol Sci |volume=17 |issue=12 |pages= |date=December 2016 |pmid=27983698 |pmc=5187913 |doi=10.3390/ijms17122113 |url=}}</ref><ref name="pmid21716157">{{cite journal |vauthors=McCluggage WG |title=Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis |journal=Pathology |volume=43 |issue=5 |pages=420–32 |date=August 2011 |pmid=21716157 |doi=10.1097/PAT.0b013e328348a6e7 |url=}}</ref>
+* '''Type II''' tumors generally arise from fallopian tubal epithelium. They exhibit more aggressive clinical course and a different genetic profile relative to '''Type I.'''<ref name="pmid27983698">{{cite journal |vauthors=Rojas V, Hirshfield KM, Ganesan S, Rodriguez-Rodriguez L |title=Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment |journal=Int J Mol Sci |volume=17 |issue=12 |pages= |date=December 2016 |pmid=27983698 |pmc=5187913 |doi=10.3390/ijms17122113 |url=}}</ref><ref name="pmid21716157">{{cite journal |vauthors=McCluggage WG |title=Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis |journal=Pathology |volume=43 |issue=5 |pages=420–32 |date=August 2011 |pmid=21716157 |doi=10.1097/PAT.0b013e328348a6e7 |url=}}</ref>
+* '''Type I''' tumors are generally characterized by chromosomal stability and somatic mutations that may include ''KRAS'', ''BRAF'', ''PTEN'', ''PIK3CA, CTNNB1'', ''ARID1A'' and ''PPP2R1A''. BRCA1 mutation, on the other hand, has not been observed and TP53 mutation is very rare.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid15111296">{{cite journal |vauthors=Shih IeM, Kurman RJ |title=Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis |journal=Am. J. Pathol. |volume=164 |issue=5 |pages=1511–8 |date=May 2004 |pmid=15111296 |doi= |url=}}</ref><ref name="pmid20942669">{{cite journal |vauthors=Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih IeM, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG |title=ARID1A mutations in endometriosis-associated ovarian carcinomas |journal=N. Engl. J. Med. |volume=363 |issue=16 |pages=1532–43 |date=October 2010 |pmid=20942669 |pmc=2976679 |doi=10.1056/NEJMoa1008433 |url=}}</ref>
+* '''Type II''' tumors are characterized by chromosomal instability. The mutations characteristic of high grade tumors, especially TP53 are common. TP53 has been reported in more than 90% of these tumors and a high proportion contains either BRCA mutations or BRCA related mutations such as RAD51, PALB2.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid20229506">{{cite journal |vauthors=Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, Stewart C, Fereday S, Caldas C, Defazio A, Bowtell D, Brenton JD |title=Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary |journal=J. Pathol. |volume=221 |issue=1 |pages=49–56 |date=May 2010 |pmid=20229506 |pmc=3262968 |doi=10.1002/path.2696 |url=}}</ref><ref name="pmid20797776">{{cite journal |vauthors=Senturk E, Cohen S, Dottino PR, Martignetti JA |title=A critical re-appraisal of BRCA1 methylation studies in ovarian cancer |journal=Gynecol. Oncol. |volume=119 |issue=2 |pages=376–83 |date=November 2010 |pmid=20797776 |doi=10.1016/j.ygyno.2010.07.026 |url=}}</ref>
+* A simplified version of this classification is provided below:
+{| class="wikitable"
+|+
+! colspan="2" style="background:#4479BA; color: #FFFFFF;" align="center" + |Epithelial Ovarian Cancer
+|-
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Type I
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Type II
+|-
+|
+* Low-grade serous carcinoma
+* Endometrioid carcinoma
+* Clear cell carcinoma
+* Mucinous carcinoma
+* Malignant Brenner tumor
+* Seromucinous carcinoma
+|
+* High-grade serous carcinoma
+* Undifferentiated carcinoma
+* Carcinosarcoma
+|}
+==== Dualistic Model for Serous Tumor ====
+* Serous tumor provides, perhaps the most, evidence for the proposed model. Studies suggest that it exhibits distinct morphological and genetic types/stages that may explain the progression from benign tumor (cystadenoma) to low grade serous tumor.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid15111296">{{cite journal |vauthors=Shih IeM, Kurman RJ |title=Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis |journal=Am. J. Pathol. |volume=164 |issue=5 |pages=1511–8 |date=May 2004 |pmid=15111296 |doi= |url=}}</ref>
+* This idea is supported by advances in discovery and understanding of so-called borderline serous tumors. These advances demonstrated that one type of these borderline tumors resembled benign serous tumors in their cinicopathological behavior and were named as “atypical proliferative serous tumor (APST)”. The other type behaved in way closer to low grade serous cancer and were termed as “micropapillary serous carcinoma (MPSC)”.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid15111296">{{cite journal |vauthors=Shih IeM, Kurman RJ |title=Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis |journal=Am. J. Pathol. |volume=164 |issue=5 |pages=1511–8 |date=May 2004 |pmid=15111296 |doi= |url=}}</ref><ref name="pmid8898836">{{cite journal |vauthors=Burks RT, Sherman ME, Kurman RJ |title=Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors |journal=Am. J. Surg. Pathol. |volume=20 |issue=11 |pages=1319–30 |date=November 1996 |pmid=8898836 |doi= |url=}}</ref>
+* The absence of KRAS and BRAF mutation in  serous cystadenoma but presence of these mutations in atypical proliferative serous tumor indicates that these mutations occur somewhat early in transformation of serous cystadenoma into atypical proliferative serous tumor.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid15466181">{{cite journal |vauthors=Ho CL, Kurman RJ, Dehari R, Wang TL, Shih IeM |title=Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors |journal=Cancer Res. |volume=64 |issue=19 |pages=6915–8 |date=October 2004 |pmid=15466181 |doi=10.1158/0008-5472.CAN-04-2067 |url=}}</ref>
+* More support was provided by studies that showed that genes involved in MAPK pathway were expressed more in micropapillary serous carcinoma than in atypical proliferative serous tumor. In addition, micropapillary serous carcinoma exhibited more chromosomal instability than atypical proliferative serous tumor.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid8898836">{{cite journal |vauthors=Burks RT, Sherman ME, Kurman RJ |title=Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors |journal=Am. J. Surg. Pathol. |volume=20 |issue=11 |pages=1319–30 |date=November 1996 |pmid=8898836 |doi= |url=}}</ref>
+* This indicates the step-wise development of low grade serous carcinoma from benign cystadenoma with developemnet of abnormalities in KRAS, BRAF and MAPK pathways. A simplistic version is given below:<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid12644542">{{cite journal |vauthors=Singer G, Oldt R, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih IeM |title=Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma |journal=J. Natl. Cancer Inst. |volume=95 |issue=6 |pages=484–6 |date=March 2003 |pmid=12644542 |doi= |url=}}</ref><ref name="pmid16806438">{{cite journal |vauthors=Mayr D, Hirschmann A, Löhrs U, Diebold J |title=KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants |journal=Gynecol. Oncol. |volume=103 |issue=3 |pages=883–7 |date=December 2006 |pmid=16806438 |doi=10.1016/j.ygyno.2006.05.029 |url=}}</ref><ref name="pmid15475429">{{cite journal |vauthors=Hsu CY, Bristow R, Cha MS, Wang BG, Ho CL, Kurman RJ, Wang TL, Shih IeM |title=Characterization of active mitogen-activated protein kinase in ovarian serous carcinomas |journal=Clin. Cancer Res. |volume=10 |issue=19 |pages=6432–6 |date=October 2004 |pmid=15475429 |doi=10.1158/1078-0432.CCR-04-0893 |url=}}</ref>
+'''ERRB2 (mutation) → PI3K → AKT → mTOR → Cyclin D1 → cell cycle control and cellular survival → Tumor initiation and progression'''
+'''↓'''
+'''KRAS → BRAF → MEK → ERK → Cell cycle control and cellular survival → Tumor initiation and progression'''
+'''PI3K (mutation) → AKT → Tumor initiation and progression'''
+'''KRAS (mutation) → BRAF → MEK → ERK → Tumor initiation and progression'''
+'''PI3K (mutation) → Tumor initiation and progression'''
+'''BRAF (mutation) → MEK → ERK → Cell cycle control and cellular survival → Tumor initiation and progression'''
+<nowiki>*</nowiki>ERK can directly promote tumor initiation, and cellular growth and survival or can promote these through activation of glucose transporter-1 and cyclin D1.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref>
+* High grade serous carcinoma, on the other hand, is characterized by mutations rarely found in either of low grade serous carcinoma, micropapillary serous carcinoma and atypical prolferative serous tumor. Of these mutations, TP53 is the most common mutation and is found in >90% of the cases.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid20797776">{{cite journal |vauthors=Senturk E, Cohen S, Dottino PR, Martignetti JA |title=A critical re-appraisal of BRCA1 methylation studies in ovarian cancer |journal=Gynecol. Oncol. |volume=119 |issue=2 |pages=376–83 |date=November 2010 |pmid=20797776 |doi=10.1016/j.ygyno.2010.07.026 |url=}}</ref>
+* While BRCA1 and BRCA2 mutations occur in majority of familial high grade serous carcinoma, inactivation of BRCA1 and/or BRCA2 by indirect mechanisms such as mutation and/or inactivation of promoter occur more frequently in sporadic high grade serous cancer and have been observed in about half of these cancers.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid20117829">{{cite journal |vauthors=May T, Virtanen C, Sharma M, Milea A, Begley H, Rosen B, Murphy KJ, Brown TJ, Shaw PA |title=Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary |journal=Gynecol. Oncol. |volume=117 |issue=1 |pages=9–17 |date=April 2010 |pmid=20117829 |doi=10.1016/j.ygyno.2010.01.006 |url=}}</ref>
+* The most noteworthy feature in molecular pathogenesis of high grade serous carcinoma is high level of DNA copy number gains or losses. These gains or losses are diffuse and include foci such as ''CCNE1'' (cyclin E1), ''NOTCH3, AKT2, RSF1'', and ''PIK3CA.''<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid17351921">{{cite journal |vauthors=Nakayama K, Nakayama N, Jinawath N, Salani R, Kurman RJ, Shih IeM, Wang TL |title=Amplicon profiles in ovarian serous carcinomas |journal=Int. J. Cancer |volume=120 |issue=12 |pages=2613–7 |date=June 2007 |pmid=17351921 |doi=10.1002/ijc.22609 |url=}}</ref>
+[[File:Pathogenesis of high grade serous carcinoma.jpg|alt=Pathogenesis of high grade serous carcinoma|center|frame|Pathogenesis of high grade serous carcinoma<ref name="pmid27898521">{{cite journal |vauthors=Kroeger PT, Drapkin R |title=Pathogenesis and heterogeneity of ovarian cancer |journal=Curr. Opin. Obstet. Gynecol. |volume=29 |issue=1 |pages=26–34 |date=February 2017 |pmid=27898521 |pmc=5201412 |doi=10.1097/GCO.0000000000000340 |url=}}</ref>
+Normal fallopian tube epithelium comprises of both secretory and ciliated cells and stains negative for p53. The benign ‘p53 signature’: secretory cells that possess strong p53 expression and evidence of DNA damage but are not proliferative. When they progress to serous tubal intraepithelial carcinoma or ‘STIC’, they acquire nuclear pleomorphism, mitoses, and loss of polarity. Serous tubal intraepithelial carcinoma shares all these properties with invasive high grade serous epithelial ovarian cancer and clinical symptoms typically emerge with advanced disease.<ref name="pmid27898521">{{cite journal |vauthors=Kroeger PT, Drapkin R |title=Pathogenesis and heterogeneity of ovarian cancer |journal=Curr. Opin. Obstet. Gynecol. |volume=29 |issue=1 |pages=26–34 |date=February 2017 |pmid=27898521 |pmc=5201412 |doi=10.1097/GCO.0000000000000340 |url=}}</ref><ref name="pmid19746182">{{cite journal |vauthors=Karst AM, Drapkin R |title=Ovarian cancer pathogenesis: a model in evolution |journal=J Oncol |volume=2010 |issue= |pages=932371 |date=2010 |pmid=19746182 |pmc=2739011 |doi=10.1155/2010/932371 |url=}}</ref>]]
+==== Genetic Alterations in Clear Cell ====
+* Inactivating mutation of ARID1A. ARID1A encodes for a product that functions in tumor suppression and is observed in half of clear cell cancers.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid20942669">{{cite journal |vauthors=Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih IeM, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG |title=ARID1A mutations in endometriosis-associated ovarian carcinomas |journal=N. Engl. J. Med. |volume=363 |issue=16 |pages=1532–43 |date=October 2010 |pmid=20942669 |pmc=2976679 |doi=10.1056/NEJMoa1008433 |url=}}</ref><ref name="pmid20826764">{{cite journal |vauthors=Jones S, Wang TL, Shih IeM, Mao TL, Nakayama K, Roden R, Glas R, Slamon D, Diaz LA, Vogelstein B, Kinzler KW, Velculescu VE, Papadopoulos N |title=Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma |journal=Science |volume=330 |issue=6001 |pages=228–31 |date=October 2010 |pmid=20826764 |pmc=3076894 |doi=10.1126/science.1196333 |url=}}</ref>
+* Activating mutation of ''PIK3CA'', also observed in about half of these tumors, results in actiavtion of PI3k pathway.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid15520168">{{cite journal |vauthors=Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA |title=Mutation of the PIK3CA gene in ovarian and breast cancer |journal=Cancer Res. |volume=64 |issue=21 |pages=7678–81 |date=November 2004 |pmid=15520168 |doi=10.1158/0008-5472.CAN-04-2933 |url=}}</ref>
+* Deletion of ''PTEN'', observed in about 20% of the cases, results in loss of tumor suppressor gene.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid11156411">{{cite journal |vauthors=Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y, Kubo T, Noguchi M |title=Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary |journal=Cancer Res. |volume=60 |issue=24 |pages=7052–6 |date=December 2000 |pmid=11156411 |doi= |url=}}</ref>
+* These alterations indicate the importance of PI3K/PTEN pathway in development of clear cell carcinoma of ovary.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid11156411">{{cite journal |vauthors=Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y, Kubo T, Noguchi M |title=Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary |journal=Cancer Res. |volume=60 |issue=24 |pages=7052–6 |date=December 2000 |pmid=11156411 |doi= |url=}}</ref>
+[[File:ARIDA loss and PIK3CA activation in clear cell cancer of ovaries.png|center|frame|'''<big>ARIDA loss and PIK3CA activation in clear cell cancer of ovaries.</big>'''<ref name="pmid256256252">{{cite journal |vauthors=Chandler RL, Damrauer JS, Raab JR, Schisler JC, Wilkerson MD, Didion JP, Starmer J, Serber D, Yee D, Xiong J, Darr DB, Pardo-Manuel  de Villena F, Kim WY, Magnuson T |title=Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling |journal=Nat Commun |volume=6 |issue= |pages=6118 |date=January 2015 |pmid=25625625 |pmc=4308813 |doi=10.1038/ncomms7118 |url=}}</ref>(A)  ARID1A and PIK3CA alterations plot against TCGA datasets. Significance of association between ARID1A and PIK3CA mutations were determined using Fisher’s exact test. (B) Determination of CRE-deleted (''Arid1aΔ'') allele in samples of tumor DNA. (C) RT-PCR was used to detect ARID1A loss or ''(Gt)Rosa26Pik3ca<sup>*H1047R</sup>'' transcripts.  (D and E) Expression of ARID1A in normal ovaries (E) Expression of ARID1A in the normal ovarian surface epithelium (arrowhead). (F) ARID1A expression is not observed in the tumors. (H, I) Highest expression of P-AKT S473 in surface epithelium of ovaries in normal ovaries (E, arrowhead) and are greatly increased in ovarian tumors (F, arrowhead). Asterisk in ''E'' denotes an oocyte. (J,K) Morbid ''Arid1a<sup>fl/fl</sup>;(Gt)Rosa26Pik3ca<sup>*H1047R</sup>'' mouse at sacrifice with hemorrhagic ascites (inset), primary ovarian tumor of moderate size, and bilateral tumor metastases (arrowheads). (L,M) Morbid ''Arid1a<sup>fl/fl</sup>;(Gt)Rosa26Pik3ca<sup>*H1047R</sup>'' mouse at sacrifice with hemorrhagic ascites (inset), large primary ovarian tumor, and no visible metastases. The mice shown in ''J-M'' were sacrificed at 7 and 9 weeks post-AdCRE, respectively, because of visible ascitic fluid burden. (N,O) ''Arid1a<sup>fl/+</sup>;(Gt)Rosa26Pik3ca<sup>*H1047R</sup>'' mice at 11-weeks post-AdCRE showing no evidence for tumor formation. In ''K'' and ''M'', dashed circles indicate primary ovarian tumor on injected ovary. In ''N'', arrows denote the AdCRE injected ovary. In ''K'', ''M'', and ''O'', asterisks denote the uninjected, control ovary.|link=https://www.wikidoc.org/index.php/File:ARIDA_loss_and_PIK3CA_activation_in_clear_cell_cancer_of_ovaries.png]]
+==== Genetic Alterations in Endometrioid Tumors ====
+* Low grade endometrioid cancer also exhibits dysregulated either PI3K/PTEN pathway or Wnt/b-catenin signaling pathway. Later has been observed in about 40% of the low grade endometrioid tumors.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid9605750">{{cite journal |vauthors=Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix-Trench G, Thomas EJ, Campbell IG |title=Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors |journal=Cancer Res. |volume=58 |issue=10 |pages=2095–7 |date=May 1998 |pmid=9605750 |doi= |url=}}</ref><ref name="pmid15668893">{{cite journal |vauthors=Catasús L, Bussaglia E, Rodrguez I, Gallardo A, Pons C, Irving JA, Prat J |title=Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas |journal=Hum. Pathol. |volume=35 |issue=11 |pages=1360–8 |date=November 2004 |pmid=15668893 |doi=10.1016/j.humpath.2004.07.019 |url=}}</ref><ref name="pmid17418409">{{cite journal |vauthors=Wu R, Hendrix-Lucas N, Kuick R, Zhai Y, Schwartz DR, Akyol A, Hanash S, Misek DE, Katabuchi H, Williams BO, Fearon ER, Cho KR |title=Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways |journal=Cancer Cell |volume=11 |issue=4 |pages=321–33 |date=April 2007 |pmid=17418409 |doi=10.1016/j.ccr.2007.02.016 |url=}}</ref>
+* PI3K/PTEN pathway is deregulated either by activating mutations in PIK3CA or inactivation/deletion of PTEN, a tumor suppressor gene. Activating mutations of ''CTNNB1'', that encodes β-catenin, are usually the cause for deregulated Wnt/b-catenin signaling pathway.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid9605750">{{cite journal |vauthors=Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix-Trench G, Thomas EJ, Campbell IG |title=Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors |journal=Cancer Res. |volume=58 |issue=10 |pages=2095–7 |date=May 1998 |pmid=9605750 |doi= |url=}}</ref><ref name="pmid15668893">{{cite journal |vauthors=Catasús L, Bussaglia E, Rodrguez I, Gallardo A, Pons C, Irving JA, Prat J |title=Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas |journal=Hum. Pathol. |volume=35 |issue=11 |pages=1360–8 |date=November 2004 |pmid=15668893 |doi=10.1016/j.humpath.2004.07.019 |url=}}</ref><ref name="pmid17418409">{{cite journal |vauthors=Wu R, Hendrix-Lucas N, Kuick R, Zhai Y, Schwartz DR, Akyol A, Hanash S, Misek DE, Katabuchi H, Williams BO, Fearon ER, Cho KR |title=Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways |journal=Cancer Cell |volume=11 |issue=4 |pages=321–33 |date=April 2007 |pmid=17418409 |doi=10.1016/j.ccr.2007.02.016 |url=}}</ref>
+* High grade endometrioid carcinoma, on the other hand, dooes not exhibit dysregulated PI3K/PTEN pathway or Wnt/b-catenin signaling pathway but frequently has TP53 mutations present.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid17418409">{{cite journal |vauthors=Wu R, Hendrix-Lucas N, Kuick R, Zhai Y, Schwartz DR, Akyol A, Hanash S, Misek DE, Katabuchi H, Williams BO, Fearon ER, Cho KR |title=Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways |journal=Cancer Cell |volume=11 |issue=4 |pages=321–33 |date=April 2007 |pmid=17418409 |doi=10.1016/j.ccr.2007.02.016 |url=}}</ref>
+==== Genetic Alterations in Mucinous Tumors ====
+* KRAS mutations are present in up to two thirds of these tumors and have also been used as molecular marker.<ref name="pmid21683865">{{cite journal |vauthors=Kurman RJ, Shih IeM |title=Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm |journal=Hum. Pathol. |volume=42 |issue=7 |pages=918–31 |date=July 2011 |pmid=21683865 |pmc=3148026 |doi=10.1016/j.humpath.2011.03.003 |url=}}</ref><ref name="pmid8261457">{{cite journal |vauthors=Ichikawa Y, Nishida M, Suzuki H, Yoshida S, Tsunoda H, Kubo T, Uchida K, Miwa M |title=Mutation of K-ras protooncogene is associated with histological subtypes in human mucinous ovarian tumors |journal=Cancer Res. |volume=54 |issue=1 |pages=33–5 |date=January 1994 |pmid=8261457 |doi= |url=}}</ref><ref name="pmid12893203">{{cite journal |vauthors=Gemignani ML, Schlaerth AC, Bogomolniy F, Barakat RR, Lin O, Soslow R, Venkatraman E, Boyd J |title=Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma |journal=Gynecol. Oncol. |volume=90 |issue=2 |pages=378–81 |date=August 2003 |pmid=12893203 |doi= |url=}}</ref>
+{| class="wikitable"
+|+
+! colspan="3" style="background:#4479BA; color: #FFFFFF;" align="center" + |Possible genetic alteration in epithelial ovarian cancers
+|-
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Protein
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Normal function
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Function in malignancy
+|-
+|style="background:#DCDCDC;" align="center" + | Human Epidermal growth factor receptor (HER-1)<ref name="pmid28513565">{{cite journal |vauthors=Wee P, Wang Z |title=Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways |journal=Cancers (Basel) |volume=9 |issue=5 |pages= |date=May 2017 |pmid=28513565 |pmc=5447962 |doi=10.3390/cancers9050052 |url=}}</ref><ref name="pmid25276427">{{cite journal |vauthors=Iqbal N, Iqbal N |title=Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications |journal=Mol Biol Int |volume=2014 |issue= |pages=852748 |date=2014 |pmid=25276427 |pmc=4170925 |doi=10.1155/2014/852748 |url=}}</ref>
+|
+* Promotes cell proliferation
+* Opposes apoptosis
+* Regulates differentiation
+|
+* Activating mutation
+* Increased cellular proliferation
+* Inhibition of apoptosis
+|-
+|style="background:#DCDCDC;" align="center" + |Human Epidermal Growth Factor Receptor 2 (HER-2)<ref name="pmid28513565">{{cite journal |vauthors=Wee P, Wang Z |title=Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways |journal=Cancers (Basel) |volume=9 |issue=5 |pages= |date=May 2017 |pmid=28513565 |pmc=5447962 |doi=10.3390/cancers9050052 |url=}}</ref><ref name="pmid25276427">{{cite journal |vauthors=Iqbal N, Iqbal N |title=Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications |journal=Mol Biol Int |volume=2014 |issue= |pages=852748 |date=2014 |pmid=25276427 |pmc=4170925 |doi=10.1155/2014/852748 |url=}}</ref>
+|
+* Promotes cell prolifeartion
+* Inhibition of apoptosis
+* Regulates differentiation
+|
+* Activating mutation
+* Increased cellular proliferation
+* Inhibition of apoptosis
+|-
+|style="background:#DCDCDC;" align="center" + |Non-receptor tyrosine kinase Src<ref name="pmid21334414">{{cite journal |vauthors=Zan L, Wu H, Jiang J, Zhao S, Song Y, Teng G, Li H, Jia Y, Zhou M, Zhang X, Qi J, Wang J |title=Temporal profile of Src, SSeCKS, and angiogenic factors after focal cerebral ischemia: correlations with angiogenesis and cerebral edema |journal=Neurochem. Int. |volume=58 |issue=8 |pages=872–9 |date=July 2011 |pmid=21334414 |pmc=3100427 |doi=10.1016/j.neuint.2011.02.014 |url=}}</ref><ref name="pmid24481818">{{cite journal |vauthors=Reinecke JB, Katafiasz D, Naslavsky N, Caplan S |title=Regulation of Src trafficking and activation by the endocytic regulatory proteins MICAL-L1 and EHD1 |journal=J. Cell. Sci. |volume=127 |issue=Pt 8 |pages=1684–98 |date=April 2014 |pmid=24481818 |pmc=3986674 |doi=10.1242/jcs.133892 |url=}}</ref>
+|Involved in regulation of
+* Gene transcription
+* Angiogenesis
+* Cellular adhesion
+* Cellular proliferation
+|
+* Activating mutation
+* Increased angiogenesis
+* Decreased cellular adhesion
+* Increased tumor metastasis
+* Increased cellular proliferation
+|-
+|style="background:#DCDCDC;" align="center" + |Colony stimulating factor-1/fms<ref name="pmid21761359">{{cite journal |vauthors=Saad AF, Hu W, Sood AK |title=Microenvironment and pathogenesis of epithelial ovarian cancer |journal=Horm Cancer |volume=1 |issue=6 |pages=277–90 |date=December 2010 |pmid=21761359 |pmc=3199131 |doi=10.1007/s12672-010-0054-2 |url=}}</ref><ref name="pmid28629162">{{cite journal |vauthors=Dwyer AR, Greenland EL, Pixley FJ |title=Promotion of Tumor Invasion by Tumor-Associated Macrophages: The Role of CSF-1-Activated Phosphatidylinositol 3 Kinase and Src Family Kinase Motility Signaling |journal=Cancers (Basel) |volume=9 |issue=6 |pages= |date=June 2017 |pmid=28629162 |pmc=5483887 |doi=10.3390/cancers9060068 |url=}}</ref><ref name="pmid19711348">{{cite journal |vauthors=Abraham D, Zins K, Sioud M, Lucas T, Schäfer R, Stanley ER, Aharinejad S |title=Stromal cell-derived CSF-1 blockade prolongs xenograft survival of CSF-1-negative neuroblastoma |journal=Int. J. Cancer |volume=126 |issue=6 |pages=1339–52 |date=March 2010 |pmid=19711348 |pmc=3222589 |doi=10.1002/ijc.24859 |url=}}</ref>
+|
+* Increased macrophage survival
+* Increased macrophage proliferation
+* Increased macrophage differentiation
+|
+* Activating mutation
+* Stimulation of tumor cell proliferation
+* Increased angiogenesis
+* Promotes tumor invasion
+* Increased metastasis
+* Decreased anoikis
+|-
+|style="background:#DCDCDC;" align="center" + |Insulin-like growth factor/receptor ILGF/ILGFR<ref name="pmid11577173">{{cite journal |vauthors=Laron Z |title=Insulin-like growth factor 1 (IGF-1): a growth hormone |journal=MP, Mol. Pathol. |volume=54 |issue=5 |pages=311–6 |date=October 2001 |pmid=11577173 |pmc=1187088 |doi= |url=}}</ref><ref name="pmid22682634">{{cite journal |vauthors=Weroha SJ, Haluska P |title=The insulin-like growth factor system in cancer |journal=Endocrinol. Metab. Clin. North Am. |volume=41 |issue=2 |pages=335–50, vi |date=June 2012 |pmid=22682634 |pmc=3614012 |doi=10.1016/j.ecl.2012.04.014 |url=}}</ref><ref name="pmid12237896">{{cite journal |vauthors=Lukanova A, Lundin E, Toniolo P, Micheli A, Akhmedkhanov A, Rinaldi S, Muti P, Lenner P, Biessy C, Krogh V, Zeleniuch-Jacquotte A, Berrino F, Hallmans G, Riboli E, Kaaks R |title=Circulating levels of insulin-like growth factor-I and risk of ovarian cancer |journal=Int. J. Cancer |volume=101 |issue=6 |pages=549–54 |date=October 2002 |pmid=12237896 |doi=10.1002/ijc.10613 |url=}}</ref>
+|
+* Promotes growth
+* Increased survival
+|
+* Activating mutation
+* Increased proliferation
+* Enhanced survival
+* Suppression of cell cycle regulators
+|-
+|style="background:#DCDCDC;" align="center" + |k-ras<ref name="pmid22589270">{{cite journal |vauthors=Prior IA, Lewis PD, Mattos C |title=A comprehensive survey of Ras mutations in cancer |journal=Cancer Res. |volume=72 |issue=10 |pages=2457–67 |date=May 2012 |pmid=22589270 |pmc=3354961 |doi=10.1158/0008-5472.CAN-11-2612 |url=}}</ref><ref name="pmid20007845">{{cite journal |vauthors=Franklin WA, Haney J, Sugita M, Bemis L, Jimeno A, Messersmith WA |title=KRAS mutation: comparison of testing methods and tissue sampling techniques in colon cancer |journal=J Mol Diagn |volume=12 |issue=1 |pages=43–50 |date=January 2010 |pmid=20007845 |pmc=2797717 |doi=10.2353/jmoldx.2010.080131 |url=}}</ref>
+|
+* Cellular proliferation
+* Cell survival
+|
+* Activating mutation
+* Increased proliferation
+* Enhanced survival
+|-
+|style="background:#DCDCDC;" align="center" + |b-raf<ref name="pmid18060073">{{cite journal |vauthors=Estep AL, Palmer C, McCormick F, Rauen KA |title=Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy |journal=PLoS ONE |volume=2 |issue=12 |pages=e1279 |date=December 2007 |pmid=18060073 |pmc=2093994 |doi=10.1371/journal.pone.0001279 |url=}}</ref><ref name="pmid22930283">{{cite journal |vauthors=Grisham RN, Iyer G, Garg K, Delair D, Hyman DM, Zhou Q, Iasonos A, Berger MF, Dao F, Spriggs DR, Levine DA, Aghajanian C, Solit DB |title=BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer |journal=Cancer |volume=119 |issue=3 |pages=548–554 |date=February 2013 |pmid=22930283 |pmc=3961140 |doi=10.1002/cncr.27782 |url=}}</ref>
+|
+* Cellular proliferation
+* Cellular differentiation
+|
+* Activating mutation
+* Increased proliferation
+* Enhanced growth
+|-
+|style="background:#DCDCDC;" align="center" + |Transforming growth factor-β<ref name="pmid28758950">{{cite journal |vauthors=Alsina-Sanchís E, Figueras A, Lahiguera A, Gil-Martín M, Pardo B, Piulats JM, Martí L, Ponce J, Matias-Guiu X, Vidal A, Villanueva A, Viñals F |title=TGFβ Controls Ovarian Cancer Cell Proliferation |journal=Int J Mol Sci |volume=18 |issue=8 |pages= |date=July 2017 |pmid=28758950 |pmc=5578048 |doi=10.3390/ijms18081658 |url=}}</ref><ref name="pmid24511106">{{cite journal |vauthors=Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, Pasche B, Lee C, Grippo PJ |title=TGF-β: duality of function between tumor prevention and carcinogenesis |journal=J. Natl. Cancer Inst. |volume=106 |issue=2 |pages=djt369 |date=February 2014 |pmid=24511106 |pmc=3952197 |doi=10.1093/jnci/djt369 |url=}}</ref><ref name="pmid20018551">{{cite journal |vauthors=Bierie B, Moses HL |title=Transforming growth factor beta (TGF-beta) and inflammation in cancer |journal=Cytokine Growth Factor Rev. |volume=21 |issue=1 |pages=49–59 |date=February 2010 |pmid=20018551 |pmc=2834863 |doi=10.1016/j.cytogfr.2009.11.008 |url=}}</ref>
+|
+* May function as a tumor suppressor and a promoter
+* Promotes growth arrest
+* Maintains cellular homeostasis
+|
+* Increased proliferation
+* Decreased apoptosis
+* Epithelial-to-mesenchymal transition
+* Sustained angiogenesis
+* Evasion of immune surveillance
+* Metastasis
+|-
+|style="background:#DCDCDC;" align="center" + |myc<ref name="pmid23071356">{{cite journal |vauthors=Miller DM, Thomas SD, Islam A, Muench D, Sedoris K |title=c-Myc and cancer metabolism |journal=Clin. Cancer Res. |volume=18 |issue=20 |pages=5546–53 |date=October 2012 |pmid=23071356 |pmc=3505847 |doi=10.1158/1078-0432.CCR-12-0977 |url=}}</ref><ref name="pmid22464321">{{cite journal |vauthors=Dang CV |title=MYC on the path to cancer |journal=Cell |volume=149 |issue=1 |pages=22–35 |date=March 2012 |pmid=22464321 |pmc=3345192 |doi=10.1016/j.cell.2012.03.003 |url=}}</ref><ref name="pmid26889675">{{cite journal |vauthors=Aughey GN, Grice SJ, Liu JL |title=The Interplay between Myc and CTP Synthase in Drosophila |journal=PLoS Genet. |volume=12 |issue=2 |pages=e1005867 |date=February 2016 |pmid=26889675 |pmc=4759343 |doi=10.1371/journal.pgen.1005867 |url=}}</ref>
+|
+* Derives cellular proliferation
+* Increased growth
+* Cell-cycle mediator
+* Inhibits apoptosis
+* Stem-cell renewal
+|
+* Activating mutation
+* Increased proliferation
+* Decreased apoptosis
+* Increased metabolism in tumor cells
+|-
+|style="background:#DCDCDC;" align="center" + |Cyclin D/Cdk4/6<ref name="pmid12802071">{{cite journal |vauthors=Neumeister P, Pixley FJ, Xiong Y, Xie H, Wu K, Ashton A, Cammer M, Chan A, Symons M, Stanley ER, Pestell RG |title=Cyclin D1 governs adhesion and motility of macrophages |journal=Mol. Biol. Cell |volume=14 |issue=5 |pages=2005–15 |date=May 2003 |pmid=12802071 |pmc=165093 |doi=10.1091/mbc.02-07-0102 |url=}}</ref><ref name="pmid29309421">{{cite journal |vauthors=Dong P, Zhang C, Parker BT, You L, Mathey-Prevot B |title=Cyclin D/CDK4/6 activity controls G1 length in mammalian cells |journal=PLoS ONE |volume=13 |issue=1 |pages=e0185637 |date=2018 |pmid=29309421 |pmc=5757913 |doi=10.1371/journal.pone.0185637 |url=}}</ref><ref name="pmid8633069">{{cite journal |vauthors=Khleif SN, DeGregori J, Yee CL, Otterson GA, Kaye FJ, Nevins JR, Howley PM |title=Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=9 |pages=4350–4 |date=April 1996 |pmid=8633069 |pmc=39540 |doi= |url=}}</ref>
+|
+* Cell-cycle mediator
+* Controls G1 length
+|
+* Activating mutation
+* Decreased G1 length
+* Increased proliferation
+* Increased angiogenesis
+|-
+|style="background:#DCDCDC;" align="center" + |Cyclin E/Cdk2<ref name="pmid15660127">{{cite journal |vauthors=Honda R, Lowe ED, Dubinina E, Skamnaki V, Cook A, Brown NR, Johnson LN |title=The structure of cyclin E1/CDK2: implications for CDK2 activation and CDK2-independent roles |journal=EMBO J. |volume=24 |issue=3 |pages=452–63 |date=February 2005 |pmid=15660127 |pmc=548659 |doi=10.1038/sj.emboj.7600554 |url=}}</ref><ref name="pmid26219338">{{cite journal |vauthors=Choudhary GS, Tat TT, Misra S, Hill BT, Smith MR, Almasan A, Mazumder S |title=Cyclin E/Cdk2-dependent phosphorylation of Mcl-1 determines its stability and cellular sensitivity to BH3 mimetics |journal=Oncotarget |volume=6 |issue=19 |pages=16912–25 |date=July 2015 |pmid=26219338 |pmc=4627281 |doi=10.18632/oncotarget.4857 |url=}}</ref><ref name="pmid8861947">{{cite journal |vauthors=Won KA, Reed SI |title=Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E |journal=EMBO J. |volume=15 |issue=16 |pages=4182–93 |date=August 1996 |pmid=8861947 |pmc=452142 |doi= |url=}}</ref>
+|
+* Cellular proliferation
+* Cell-cycle mediator
+* Assembly of the pre-replication complex
+* Promotes G0 to cell cycle entry
+* Promotes G1 to S phase transition
+* Decreased apoptosis
+|
+* Activating mutation
+* Increased cellular proliferation
+* Impaired apoptosis
+* Increased cellular survival
+|-
+|style="background:#DCDCDC;" align="center" + |Cyclin B/Cdk1<ref name="pmid28489780">{{cite journal |vauthors=Sun X, Zhangyuan G, Shi L, Wang Y, Sun B, Ding Q |title=Prognostic and clinicopathological significance of cyclin B expression in patients with breast cancer: A meta-analysis |journal=Medicine (Baltimore) |volume=96 |issue=19 |pages=e6860 |date=May 2017 |pmid=28489780 |pmc=5428614 |doi=10.1097/MD.0000000000006860 |url=}}</ref><ref name="pmid24324638">{{cite journal |vauthors=Huang Y, Sramkoski RM, Jacobberger JW |title=The kinetics of G2 and M transitions regulated by B cyclins |journal=PLoS ONE |volume=8 |issue=12 |pages=e80861 |date=2013 |pmid=24324638 |pmc=3851588 |doi=10.1371/journal.pone.0080861 |url=}}</ref><ref name="pmid17472438">{{cite journal |vauthors=Lindqvist A, van Zon W, Karlsson Rosenthal C, Wolthuis RM |title=Cyclin B1-Cdk1 activation continues after centrosome separation to control mitotic progression |journal=PLoS Biol. |volume=5 |issue=5 |pages=e123 |date=May 2007 |pmid=17472438 |pmc=1858714 |doi=10.1371/journal.pbio.0050123 |url=}}</ref>
+|
+* Cell-cycle mediator
+* promotes G2 to M phase transition
+|
+* Activating mutation
+* Increased cellular proliferation
+* Promotes malignant transformation
+|-
+|style="background:#DCDCDC;" align="center" + |p16<ref name="pmid27572321">{{cite journal |vauthors=Yoon N, Yoon G, Park CK, Kim HS |title=Stromal p16 expression is significantly increased in malignant ovarian neoplasms |journal=Oncotarget |volume=7 |issue=40 |pages=64665–64673 |date=October 2016 |pmid=27572321 |pmc=5323106 |doi=10.18632/oncotarget.11660 |url=}}</ref><ref name="pmid9846965">{{cite journal |vauthors=Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T |title=Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions |journal=Am. J. Pathol. |volume=153 |issue=6 |pages=1741–8 |date=December 1998 |pmid=9846965 |pmc=1866324 |doi=10.1016/S0002-9440(10)65689-1 |url=}}</ref><ref name="pmid25709969">{{cite journal |vauthors=Felix AS, Sherman ME, Hewitt SM, Gunja MZ, Yang HP, Cora RL, Boudreau V, Ylaya K, Lissowska J, Brinton LA, Wentzensen N |title=Cell-cycle protein expression in a population-based study of ovarian and endometrial cancers |journal=Front Oncol |volume=5 |issue= |pages=25 |date=2015 |pmid=25709969 |pmc=4321403 |doi=10.3389/fonc.2015.00025 |url=}}</ref>
+|
+* Member of the INK4 family of CDK inhibitors
+* Inhibits Cyclin D/Cdk4/6
+* Decreased G1 to S phase transition
+|
+* Lost or downregulated
+* Decreased G1 length
+* Increased proliferation
+* Increased angiogenesis
+|-
+|style="background:#DCDCDC;" align="center" + |p27 (kip-1)<ref name="pmid19887899">{{cite journal |vauthors=Lee J, Kim SS |title=The function of p27 KIP1 during tumor development |journal=Exp. Mol. Med. |volume=41 |issue=11 |pages=765–71 |date=November 2009 |pmid=19887899 |pmc=2788730 |doi=10.3858/emm.2009.41.11.102 |url=}}</ref><ref name="pmid18583941">{{cite journal |vauthors=Roy S, Singh RP, Agarwal C, Siriwardana S, Sclafani R, Agarwal R |title=Downregulation of both p21/Cip1 and p27/Kip1 produces a more aggressive prostate cancer phenotype |journal=Cell Cycle |volume=7 |issue=12 |pages=1828–35 |date=June 2008 |pmid=18583941 |pmc=2744498 |doi=10.4161/cc.7.12.6024 |url=}}</ref><ref name="pmid11438653">{{cite journal |vauthors=Miskimins WK, Wang G, Hawkinson M, Miskimins R |title=Control of cyclin-dependent kinase inhibitor p27 expression by cap-independent translation |journal=Mol. Cell. Biol. |volume=21 |issue=15 |pages=4960–7 |date=August 2001 |pmid=11438653 |pmc=87223 |doi=10.1128/MCB.21.15.4960-4967.2001 |url=}}</ref>
+|
+* Inhibitor of Cyclin E/Cdk2
+* Mediates cell cycle arrest
+* Decreased G1 to S phase transition
+* May act as oncogen and promote proliferation
+|
+* Lost or dysregulated
+* Increase in cell proliferation
+* Impaired apoptosis
+|-
+|style="background:#DCDCDC;" align="center" + |p21 (WAF-1)<ref name="pmid19440234">{{cite journal |vauthors=Abbas T, Dutta A |title=p21 in cancer: intricate networks  and multiple activities |journal=Nat. Rev. Cancer |volume=9 |issue=6 |pages=400–14 |date=June 2009 |pmid=19440234 |pmc=2722839 |doi=10.1038/nrc2657 |url=}}</ref><ref name="pmid15798220">{{cite journal |vauthors=Dash BC, El-Deiry WS |title=Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity |journal=Mol. Cell. Biol. |volume=25 |issue=8 |pages=3364–87 |date=April 2005 |pmid=15798220 |pmc=1069593 |doi=10.1128/MCB.25.8.3364-3387.2005 |url=}}</ref><ref name="pmid8912526">{{cite journal |vauthors=Shi Y, Zou M, Farid NR, al-Sedairy ST |title=Evidence of gene deletion of p21 (WAF1/CIP1), a cyclin-dependent protein kinase inhibitor, in thyroid carcinomas |journal=Br. J. Cancer |volume=74 |issue=9 |pages=1336–41 |date=November 1996 |pmid=8912526 |pmc=2074763 |doi= |url=}}</ref>
+|
+* Inhibits cyclin-dependant kinases
+* Cell-cycle arrest
+* Decreased proliferation
+* Promotes cellular differentiation
+* May inhibit/promote apoptosis
+* May act as oncogen and promote proliferation
+|
+* Lost or dysregulated
+* Increase in cell proliferation
+* Decreased cellular differentiation
+* Decreased apoptosis
+* Correlates positively
+** tumour grade
+** invasiveness
+** aggressiveness
+|-
+|style="background:#DCDCDC;" align="center" + |Nuclear factor-κB<ref name="pmid20457564">{{cite journal |vauthors=Lawrence T |title=The nuclear factor NF-kappaB pathway in inflammation |journal=Cold Spring Harb Perspect Biol |volume=1 |issue=6 |pages=a001651 |date=December 2009 |pmid=20457564 |pmc=2882124 |doi=10.1101/cshperspect.a001651 |url=}}</ref><ref name="pmid21339307">{{cite journal |vauthors=Yang G, Xiao X, Rosen DG, Cheng X, Wu X, Chang B, Liu G, Xue F, Mercado-Uribe I, Chiao P, Du X, Liu J |title=The biphasic role of NF-kappaB in progression and chemoresistance of ovarian cancer |journal=Clin. Cancer Res. |volume=17 |issue=8 |pages=2181–94 |date=April 2011 |pmid=21339307 |pmc=3152795 |doi=10.1158/1078-0432.CCR-10-3265 |url=}}</ref><ref name="pmid24272484">{{cite journal |vauthors=Charbonneau B, Block MS, Bamlet WR, Vierkant RA, Kalli KR, Fogarty Z, Rider DN, Sellers TA, Tworoger SS, Poole E, Risch HA, Salvesen HB, Kiemeney LA, Baglietto L, Giles GG, Severi G, Trabert B, Wentzensen N, Chenevix-Trench G, Whittemore AS, Sieh W, Chang-Claude J, Bandera EV, Orlow I, Terry K, Goodman MT, Thompson PJ, Cook LS, Rossing MA, Ness RB, Narod SA, Kupryjanczyk J, Lu K, Butzow R, Dörk T, Pejovic T, Campbell I, Le ND, Bunker CH, Bogdanova N, Runnebaum IB, Eccles D, Paul J, Wu AH, Gayther SA, Hogdall E, Heitz F, Kaye SB, Karlan BY, Anton-Culver H, Gronwald J, Hogdall CK, Lambrechts D, Fasching PA, Menon U, Schildkraut J, Pearce CL, Levine DA, Kjaer SK, Cramer D, Flanagan JM, Phelan CM, Brown R, Massuger LF, Song H, Doherty JA, Krakstad C, Liang D, Odunsi K, Berchuck A, Jensen A, Lubinski J, Nevanlinna H, Bean YT, Lurie G, Ziogas A, Walsh C, Despierre E, Brinton L, Hein A, Rudolph A, Dansonka-Mieszkowska A, Olson SH, Harter P, Tyrer J, Vitonis AF, Brooks-Wilson A, Aben KK, Pike MC, Ramus SJ, Wik E, Cybulski C, Lin J, Sucheston L, Edwards R, McGuire V, Lester J, du Bois A, Lundvall L, Wang-Gohrke S, Szafron LM, Lambrechts S, Yang H, Beckmann MW, Pelttari LM, Van Altena AM, van den Berg D, Halle MK, Gentry-Maharaj A, Schwaab I, Chandran U, Menkiszak J, Ekici AB, Wilkens LR, Leminen A, Modugno F, Friel G, Rothstein JH, Vergote I, Garcia-Closas M, Hildebrandt MA, Sobiczewski P, Kelemen LE, Pharoah PD, Moysich K, Knutson KL, Cunningham JM, Fridley BL, Goode EL |title=Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10 |journal=Cancer Res. |volume=74 |issue=3 |pages=852–61 |date=February 2014 |pmid=24272484 |pmc=3946482 |doi=10.1158/0008-5472.CAN-13-1051 |url=}}</ref>
+|
+* A transcription factor involved in regulation of
+** immune response to inflammation
+** expression of cytokines, chemokines, and adhesion molecules
+** cell cycle
+** apoptosis
+* May function as a tumor suppressor and a promoter
+|
+* Dysregulated
+* Increased angiogenesis
+* Enhanced tumor growth
+* Induces resistance to chemotherapy by acting as anti-apoptosis
+|-
+|style="background:#DCDCDC;" align="center" + |NOEY(ARHI)<ref name="pmid21643014">{{cite journal |vauthors=Badgwell DB, Lu Z, Le K, Gao F, Yang M, Suh GK, Bao JJ, Das P, Andreeff M, Chen W, Yu Y, Ahmed AA, S-L Liao W, Bast RC |title=The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways |journal=Oncogene |volume=31 |issue=1 |pages=68–79 |date=January 2012 |pmid=21643014 |pmc=3170676 |doi=10.1038/onc.2011.213 |url=}}</ref><ref name="pmid9874798">{{cite journal |vauthors=Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC |title=NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=1 |pages=214–9 |date=January 1999 |pmid=9874798 |pmc=15119 |doi= |url=}}</ref><ref name="pmid7559524">{{cite journal |vauthors=Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG |title=Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions |journal=J. Biol. Chem. |volume=270 |issue=40 |pages=23589–97 |date=October 1995 |pmid=7559524 |doi= |url=}}</ref><ref name="pmid23591839">{{cite journal |vauthors=Dobbin ZC, Landen CN |title=The importance of the PI3K/AKT/MTOR pathway in the progression of ovarian cancer |journal=Int J Mol Sci |volume=14 |issue=4 |pages=8213–27 |date=April 2013 |pmid=23591839 |pmc=3645739 |doi=10.3390/ijms14048213 |url=}}</ref>
+|
+* Inhibits cell growth
+* Induces apoptosis
+* Inhibits tumor cells migration through chemotaxis and haptotaxis
+|
+* Inactivating mutation
+* Enhanced tumor growth
+* Decreased apoptosis
+* Increased chances for metastasis
+|-
+|style="background:#DCDCDC;" align="center" + |PIP3/Akt<ref name="pmid22952397">{{cite journal |vauthors=Hemmings BA, Restuccia DF |title=PI3K-PKB/Akt pathway |journal=Cold Spring Harb Perspect Biol |volume=4 |issue=9 |pages=a011189 |date=September 2012 |pmid=22952397 |pmc=3428770 |doi=10.1101/cshperspect.a011189 |url=}}</ref><ref name="pmid30334567">{{cite journal |vauthors=Nitulescu GM, Van De Venter M, Nitulescu G, Ungurianu A, Juzenas P, Peng Q, Olaru OT, Grădinaru D, Tsatsakis A, Tsoukalas D, Spandidos DA, Margina D |title=The Akt pathway in oncology therapy and beyond (Review) |journal=Int. J. Oncol. |volume=53 |issue=6 |pages=2319–2331 |date=December 2018 |pmid=30334567 |pmc=6203150 |doi=10.3892/ijo.2018.4597 |url=}}</ref>
+|
+* Akt is activated by PIP3 and plays a role in
+** regulation of cellular growth
+** cell cycle progression
+** regulation of glucose metabolism
+** genome stability
+** gene transcription
+** protein synthesis
+** neovascularization
+** promotes cell survival by blocking apoptosis
+|
+* Activating mutations
+* Increased cellular proliferation
+* Increased tumor cells survival
+* Increased tumor cells migration
+* Increased tumor cells invasion
+* Chemotherapy resistance
+* Decreased apoptosis
+* May promote angiogenesis
+|-
+|style="background:#DCDCDC;" align="center" + |PTEN<ref name="pmid23223894">{{cite journal |vauthors=Shi Y, Paluch BE, Wang X, Jiang X |title=PTEN at a glance |journal=J. Cell. Sci. |volume=125 |issue=Pt 20 |pages=4687–92 |date=October 2012 |pmid=23223894 |pmc=3517091 |doi=10.1242/jcs.093765 |url=}}</ref><ref name="pmid24170201">{{cite journal |vauthors=Tanwar PS, Mohapatra G, Chiang S, Engler DA, Zhang L, Kaneko-Tarui T, Ohguchi Y, Birrer MJ, Teixeira JM |title=Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer |journal=Carcinogenesis |volume=35 |issue=3 |pages=546–53 |date=March 2014 |pmid=24170201 |pmc=3941742 |doi=10.1093/carcin/bgt357 |url=}}</ref><ref name="pmid25361917">{{cite journal |vauthors=Hopkins BD, Parsons RE |title=Molecular pathways: intercellular PTEN and the potential of PTEN restoration therapy |journal=Clin. Cancer Res. |volume=20 |issue=21 |pages=5379–83 |date=November 2014 |pmid=25361917 |pmc=4362520 |doi=10.1158/1078-0432.CCR-13-2661 |url=}}</ref>
+|
+* Suppresses Akt and thus regulates cell cycle, cellular growth and apoptosis
+* Regulates self-renewal and differentiation of human stem cells
+* Regulates oocyte growth and follicular activation
+* Regulates chemotaxis of neutrophils
+* Inhibit cell invasion and migration
+|
+* Deletion or inactivating mutation
+* Increased cellular proliferation
+* Increased tumor cells survival
+* Increased tumor cells migration
+* Increased tumor cells invasion
+* Decreased apoptosis
+|-
+|style="background:#DCDCDC;" align="center" + |p53<ref name="pmid20066118">{{cite journal |vauthors=Zilfou JT, Lowe SW |title=Tumor suppressive functions of p53 |journal=Cold Spring Harb Perspect Biol |volume=1 |issue=5 |pages=a001883 |date=November 2009 |pmid=20066118 |pmc=2773645 |doi=10.1101/cshperspect.a001883 |url=}}</ref><ref name="pmid24212651">{{cite journal |vauthors=Ozaki T, Nakagawara A |title=Role of p53 in Cell Death and Human Cancers |journal=Cancers (Basel) |volume=3 |issue=1 |pages=994–1013 |date=March 2011 |pmid=24212651 |pmc=3756401 |doi=10.3390/cancers3010994 |url=}}</ref><ref name="pmid30613473">{{cite journal |vauthors=Zhang Y, Cao L, Nguyen D, Lu H |title=TP53 mutations in epithelial ovarian cancer |journal=Transl Cancer Res |volume=5 |issue=6 |pages=650–663 |date=December 2016 |pmid=30613473 |pmc=6320227 |doi=10.21037/tcr.2016.08.40 |url=}}</ref>
+|
+* A transcription factor that
+** regulates cell cycle
+** promotes DNA damage repair
+** promotes apoptosis
+** maintains genomic integrity
+|
+* Loss results in
+** DNA damage and carcinogenesis
+** increased tumor cell growth and survival
+** increased metastasis
+** decreased apoptosis
+** resistance to chemotherapy
+|-
+|style="background:#DCDCDC;" align="center" + |BRCA1<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid28794804">{{cite journal |vauthors=Neff RT, Senter L, Salani R |title=BRCA mutation in ovarian cancer: testing, implications and treatment considerations |journal=Ther Adv Med Oncol |volume=9 |issue=8 |pages=519–531 |date=August 2017 |pmid=28794804 |pmc=5524247 |doi=10.1177/1758834017714993 |url=}}</ref><ref name="pmid16484695">{{cite journal |vauthors=Chen S, Iversen ES, Friebel T, Finkelstein D, Weber BL, Eisen A, Peterson LE, Schildkraut JM, Isaacs C, Peshkin BN, Corio C, Leondaridis L, Tomlinson G, Dutson D, Kerber R, Amos CI, Strong LC, Berry DA, Euhus DM, Parmigiani G |title=Characterization of BRCA1 and BRCA2 mutations in a large United States sample |journal=J. Clin. Oncol. |volume=24 |issue=6 |pages=863–71 |date=February 2006 |pmid=16484695 |pmc=2323978 |doi=10.1200/JCO.2005.03.6772 |url=}}</ref>
+|
+* A tumor suppressor that mediates double stranded DNA repair through
+** homologous recombination pathway
+** non-homologous end joining pathway
+* Activates checkpoints in cell cycle
+* Maintains genomic integrity
+|
+* Mutations are responsible for hereditary breast & ovarian tumors
+* Loss results in
+** DNA damage and carcinogenesis
+** increased tumor cell growth and survival
+|-
+|style="background:#DCDCDC;" align="center" + |BRCA2<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid28794804">{{cite journal |vauthors=Neff RT, Senter L, Salani R |title=BRCA mutation in ovarian cancer: testing, implications and treatment considerations |journal=Ther Adv Med Oncol |volume=9 |issue=8 |pages=519–531 |date=August 2017 |pmid=28794804 |pmc=5524247 |doi=10.1177/1758834017714993 |url=}}</ref><ref name="pmid16484695">{{cite journal |vauthors=Chen S, Iversen ES, Friebel T, Finkelstein D, Weber BL, Eisen A, Peterson LE, Schildkraut JM, Isaacs C, Peshkin BN, Corio C, Leondaridis L, Tomlinson G, Dutson D, Kerber R, Amos CI, Strong LC, Berry DA, Euhus DM, Parmigiani G |title=Characterization of BRCA1 and BRCA2 mutations in a large United States sample |journal=J. Clin. Oncol. |volume=24 |issue=6 |pages=863–71 |date=February 2006 |pmid=16484695 |pmc=2323978 |doi=10.1200/JCO.2005.03.6772 |url=}}</ref>
+|
+* A tumor suppressor that mediates double stranded DNA repair through
+** homologous recombination pathway
+* Maintains genomic integrity
+* Protects replication fork and replication fidelity
+|
+* Mutations are responsible for hereditary breast & ovarian tumors
+* Loss results in
+** DNA damage and carcinogenesis
+** increased tumor cell growth and survival
+* Defects in maintenance the length of the nascent strand of DNA
+|-
+|style="background:#DCDCDC;" align="center" + |MLH1/MSH2<ref name="pmid24484585">{{cite journal |vauthors=Vymetalkova VP, Slyskova J, Korenkova V, Bielik L, Langerova L, Prochazka P, Rejhova A, Schwarzova L, Pardini B, Naccarati A, Vodicka P |title=Molecular characteristics of mismatch repair genes in sporadic colorectal tumors in Czech patients |journal=BMC Med. Genet. |volume=15 |issue= |pages=17 |date=January 2014 |pmid=24484585 |pmc=3913626 |doi=10.1186/1471-2350-15-17 |url=}}</ref><ref name="pmid21140452">{{cite journal |vauthors=Murphy MA, Wentzensen N |title=Frequency of mismatch repair deficiency in ovarian cancer: a systematic review This article is a US Government work and, as such, is in the public domain of the United States of America |journal=Int. J. Cancer |volume=129 |issue=8 |pages=1914–22 |date=October 2011 |pmid=21140452 |pmc=3107885 |doi=10.1002/ijc.25835 |url=}}</ref><ref name="pmid26710976">{{cite journal |vauthors=Heinen CD |title=Mismatch repair defects and Lynch syndrome: The role of the basic scientist in the battle against cancer |journal=DNA Repair (Amst.) |volume=38 |issue= |pages=127–34 |date=February 2016 |pmid=26710976 |pmc=4740212 |doi=10.1016/j.dnarep.2015.11.025 |url=}}</ref>
+|
+* Tumor suppressors that
+* mediates DNA damage repair
+* maintains genomic integrity
+* possible regulation of cell cycle
+|
+* Loss results in
+** DNA damage and carcinogenesis
+** increased survival
+** resistance to chemotherapy
+** chromosomal instability
+** microsatellite instability (MSI)
+** the cytosine phosphate guanine (CpG) island methylator phenotype (CIMP)
+|-
+|style="background:#DCDCDC;" align="center" + |Fas ligand<ref name="pmid25656654">{{cite journal |vauthors=Peter ME, Hadji A, Murmann AE, Brockway S, Putzbach W, Pattanayak A, Ceppi P |title=The role of CD95 and CD95 ligand in cancer |journal=Cell Death Differ. |volume=22 |issue=4 |pages=549–59 |date=April 2015 |pmid=25656654 |pmc=4356349 |doi=10.1038/cdd.2015.3 |url=}}</ref><ref name="pmid14609433">{{cite journal |vauthors=Fraser M, Leung B, Jahani-Asl A, Yan X, Thompson WE, Tsang BK |title=Chemoresistance in human ovarian cancer: the role of apoptotic regulators |journal=Reprod. Biol. Endocrinol. |volume=1 |issue= |pages=66 |date=October 2003 |pmid=14609433 |pmc=270001 |doi=10.1186/1477-7827-1-66 |url=}}</ref><ref name="pmid7520535">{{cite journal |vauthors=Lowin B, Hahne M, Mattmann C, Tschopp J |title=Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways |journal=Nature |volume=370 |issue=6491 |pages=650–2 |date=August 1994 |pmid=7520535 |doi=10.1038/370650a0 |url=}}</ref>
+|
+* Binds to Fas receptor and induces apoptosis
+* Expressed mainly on T-lymphocytes
+* May induce apoptosis in cancer cells and virus infected cells
+* May also be involved in
+** liver regeneration following partial hepatectomy
+** neurite outgrowth
+|
+* Most tumor cells are resistant to Fas-FasL mediated apoptosis
+* Tumor cells express FasL to induce apoptosis in cytotoxic lymphocytes
+* Promotes tumor cells survival
+* Enhances tumor cells invasion
+* Increased tumor cells migration
+|-
+|style="background:#DCDCDC;" align="center" + |Human leukocyte antigen-G<ref name="pmid27652273">{{cite journal |vauthors=Morandi F, Rizzo R, Fainardi E, Rouas-Freiss N, Pistoia V |title=Recent Advances in Our Understanding of HLA-G Biology: Lessons from a Wide Spectrum of Human Diseases |journal=J Immunol Res |volume=2016 |issue= |pages=4326495 |date=2016 |pmid=27652273 |pmc=5019910 |doi=10.1155/2016/4326495 |url=}}</ref><ref name="pmid26322846">{{cite journal |vauthors=Lin A, Yan WH |title=Human Leukocyte Antigen-G (HLA-G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy |journal=Mol. Med. |volume=21 |issue=1 |pages=782–791 |date=November 2015 |pmid=26322846 |pmc=4749493 |doi=10.2119/molmed.2015.00083 |url=}}</ref><ref name="pmid17681474">{{cite journal |vauthors=Sheu JJ, Shih IeM |title=Clinical and biological significance of HLA-G expression in ovarian cancer |journal=Semin. Cancer Biol. |volume=17 |issue=6 |pages=436–43 |date=December 2007 |pmid=17681474 |pmc=2151836 |doi=10.1016/j.semcancer.2007.06.012 |url=}}</ref>
+|
+* Inhibits T-cell function through
+** inhibiting proliferation
+** causing cytotoxicity
+** inducing apoptosis
+** cytokine production in B lymphocytes
+** inhibiting differentiation
+* Inhibits proliferation and cytotoxicity of natural killer cells
+* Promotes angiogenesis
+* Inhibits chemotaxis
+|
+* Promotes progression of cancer through evasion of immune response by
+** inhibiting T-cell functions by inducing apoptosis and decreased proliferation
+** inhibiting T-cell differentiation through various mechanisms
+* Inhibits proliferation and cytotoxicity of natural killer cells
+* Promotes angiogenesis
+* Inhibits chemotaxis of cytotoxic cells
+|-
+|style="background:#DCDCDC;" align="center" + |hTERT<ref name="pmid26823830">{{cite journal |vauthors=Lee YK, Chung HH, Kim JW, Song YS, Park NH |title=Expression of phosphorylated Akt and hTERT is associated with prognosis of epithelial ovarian carcinoma |journal=Int J Clin Exp Pathol |volume=8 |issue=11 |pages=14971–6 |date=2015 |pmid=26823830 |pmc=4713616 |doi= |url=}}</ref><ref name="pmid27548225">{{cite journal |vauthors=Ramlee MK, Wang J, Toh WX, Li S |title=Transcription Regulation of the Human Telomerase Reverse Transcriptase (hTERT) Gene |journal=Genes (Basel) |volume=7 |issue=8 |pages= |date=August 2016 |pmid=27548225 |pmc=4999838 |doi=10.3390/genes7080050 |url=}}</ref><ref name="pmid29526163">{{cite journal |vauthors=Leão R, Apolónio JD, Lee D, Figueiredo A, Tabori U, Castelo-Branco P |title=Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer |journal=J. Biomed. Sci. |volume=25 |issue=1 |pages=22 |date=March 2018 |pmid=29526163 |pmc=5846307 |doi=10.1186/s12929-018-0422-8 |url=}}</ref>
+|
+* Maintains telomeres length
+* Promotes replication
+|
+* Up-regulated in majority of human cancers
+* Provides limitless replication ability to cancer cells
+|-
+|style="background:#DCDCDC;" align="center" + |Vascular endothelial growth factor/Vascular endothelial
+growth factor receptor<ref name="pmid22101807">{{cite journal |vauthors=Masoumi Moghaddam S, Amini A, Morris DL, Pourgholami MH |title=Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer |journal=Cancer Metastasis Rev. |volume=31 |issue=1-2 |pages=143–62 |date=June 2012 |pmid=22101807 |pmc=3350632 |doi=10.1007/s10555-011-9337-5 |url=}}</ref><ref name="pmid24263190">{{cite journal |vauthors=Goel HL, Mercurio AM |title=VEGF targets the tumour cell |journal=Nat. Rev. Cancer |volume=13 |issue=12 |pages=871–82 |date=December 2013 |pmid=24263190 |pmc=4011842 |doi=10.1038/nrc3627 |url=}}</ref><ref name="pmid10487612">{{cite journal |vauthors=Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, Watanabe Y, Pass HI |title=VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours |journal=Br. J. Cancer |volume=81 |issue=1 |pages=54–61 |date=September 1999 |pmid=10487612 |pmc=2374345 |doi=10.1038/sj.bjc.6690650 |url=}}</ref>
+|
+* Stimulates angiogenesis through
+** increased endothelial cell survival
+** Increased endothelial cell proliferation
+** increased endothelial cell migration
+* Increases vascular permeability
+* May regulate fibroblasts in the stroma of tumors
+* May effect tumor stem cells
+|
+* Promotes angiogenesis
+* Promotes tumor cells growth
+* May initiate carcinogenesis
+* Promotes invasion and metastasis of tumor cells
+|-
+|style="background:#DCDCDC;" align="center" + |Interleukin-8<ref name="pmid27348007">{{cite journal |vauthors=David JM, Dominguez C, Hamilton DH, Palena C |title=The IL-8/IL-8R Axis: A Double Agent in Tumor Immune Resistance |journal=Vaccines (Basel) |volume=4 |issue=3 |pages= |date=June 2016 |pmid=27348007 |pmc=5041016 |doi=10.3390/vaccines4030022 |url=}}</ref><ref name="pmid29507619">{{cite journal |vauthors=Yung MM, Tang HW, Cai PC, Leung TH, Ngu SF, Chan KK, Xu D, Yang H, Ngan HY, Chan DW |title=GRO-α and IL-8 enhance ovarian cancer metastatic potential via the CXCR2-mediated TAK1/NFκB signaling cascade |journal=Theranostics |volume=8 |issue=5 |pages=1270–1285 |date=2018 |pmid=29507619 |pmc=5835935 |doi=10.7150/thno.22536 |url=}}</ref><ref name="pmid22015448">{{cite journal |vauthors=Escudero-Lourdes C, Wu T, Camarillo JM, Gandolfi AJ |title=Interleukin-8 (IL-8) over-production and autocrine cell activation are key factors in monomethylarsonous acid [MMA(III)]-induced malignant transformation of urothelial cells |journal=Toxicol. Appl. Pharmacol. |volume=258 |issue=1 |pages=10–8 |date=January 2012 |pmid=22015448 |pmc=3254786 |doi=10.1016/j.taap.2011.10.002 |url=}}</ref>
+|
+* Chemokine produced to recruit leukocytes and myeloid-derived suppressor cells
+* Promotes epithelial-to-mesenchymal transition
+* Promotes infection resolution
+* Promotes angiogenesis
+|
+* Promotes epithelial-to-mesenchymal transition in tumor cells
+* Promotes resistance to chemotherapy
+* Tumor progression through immunosuppressive and pro-tumorigenic immune cells
+* Promotes angiogenesis
+* Promotes invasion and metastasis
+|-
+|style="background:#DCDCDC;" align="center" + |EphA2<ref name="pmid24705208">{{cite journal |vauthors=Park JE, Son AI, Zhou R |title=Roles of EphA2 in Development and Disease |journal=Genes (Basel) |volume=4 |issue=3 |pages=334–57 |date=July 2013 |pmid=24705208 |pmc=3924825 |doi=10.3390/genes4030334 |url=}}</ref><ref name="pmid26283684">{{cite journal |vauthors=Dunne PD, Dasgupta S, Blayney JK, McArt DG, Redmond KL, Weir JA, Bradley CA, Sasazuki T, Shirasawa S, Wang T, Srivastava S, Ong CW, Arthur K, Salto-Tellez M, Wilson RH, Johnston PG, Van Schaeybroeck S |title=EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer |journal=Clin. Cancer Res. |volume=22 |issue=1 |pages=230–242 |date=January 2016 |pmid=26283684 |pmc=4694030 |doi=10.1158/1078-0432.CCR-15-0603 |url=}}</ref><ref name="pmid18443431">{{cite journal |vauthors=Lu C, Shahzad MM, Wang H, Landen CN, Kim SW, Allen J, Nick AM, Jennings N, Kinch MS, Bar-Eli M, Sood AK |title=EphA2 overexpression promotes ovarian cancer growth |journal=Cancer Biol. Ther. |volume=7 |issue=7 |pages=1098–103 |date=July 2008 |pmid=18443431 |pmc=2705979 |doi= |url=}}</ref>
+|
+* Promotes angiogenesis
+* Plays a key role in development of
+** Lens
+** Inner ear
+** Mammary glands
+* Promotes kidney repair following injury
+* Promotes bone remodeling bone remodeling
+|
+* Over-expressed in ovarian epithelial cancer
+* Promotes tumor initiation
+* Promotes neo-vascularization
+* Promotes tumor invasion
+* Promotes metastasis
+|-
+|style="background:#DCDCDC;" align="center" + |Matrix metalloproteinases<ref name="pmid17318226">{{cite journal |vauthors=Page-McCaw A, Ewald AJ, Werb Z |title=Matrix metalloproteinases and the regulation of tissue remodelling |journal=Nat. Rev. Mol. Cell Biol. |volume=8 |issue=3 |pages=221–33 |date=March 2007 |pmid=17318226 |pmc=2760082 |doi=10.1038/nrm2125 |url=}}</ref><ref name="pmid25945285">{{cite journal |vauthors=Caley MP, Martins VL, O'Toole EA |title=Metalloproteinases and Wound Healing |journal=Adv Wound Care (New Rochelle) |volume=4 |issue=4 |pages=225–234 |date=April 2015 |pmid=25945285 |pmc=4397992 |doi=10.1089/wound.2014.0581 |url=}}</ref><ref name="pmid25918438">{{cite journal |vauthors=Al-Alem L, Curry TE |title=Ovarian cancer: involvement of the matrix metalloproteinases |journal=Reproduction |volume=150 |issue=2 |pages=R55–64 |date=August 2015 |pmid=25918438 |pmc=4955511 |doi=10.1530/REP-14-0546 |url=}}</ref>
+|
+* Proteases that degrade tissues, matrix and other proteins and play a role in
+** bone modeling and remodeling
+** mammary development
+** blood vessels remodeling
+** a variety of other tissues such as tracheal tube
+* Promotes inflammation through enzymatic activation
+|
+* Over-expressed in ovarian epithelial cancer
+* Promotes tumor invasion through degradation of extra-cellular matrix
+* Promotes metastasis through degradation of extra-cellular matrix
+* May have a role in tumor initiation and angiogenesis
+|-
+|style="background:#DCDCDC;" align="center" + |αvβ3<ref name="pmid18998200">{{cite journal |vauthors=Cai WJ, Li MB, Wu X, Wu S, Zhu W, Chen D, Luo M, Eitenmüller I, Kampmann A, Schaper J, Schaper W |title=Activation of the integrins alpha 5beta 1 and alpha v beta 3 and focal adhesion kinase (FAK) during arteriogenesis |journal=Mol. Cell. Biochem. |volume=322 |issue=1-2 |pages=161–9 |date=February 2009 |pmid=18998200 |pmc=2758386 |doi=10.1007/s11010-008-9953-8 |url=}}</ref><ref name="pmid20628538">{{cite journal |vauthors=Liu Z, Wang F, Chen X |title=Integrin alpha(v)beta(3)-Targeted Cancer Therapy |journal=Drug Dev. Res. |volume=69 |issue=6 |pages=329–339 |date=2008 |pmid=20628538 |pmc=2901818 |doi=10.1002/ddr.20265 |url=}}</ref><ref name="pmid29548784">{{cite journal |vauthors=Shaw SK, Schreiber CL, Roland FM, Battles PM, Brennan SP, Padanilam SJ, Smith BD |title=High expression of integrin αvβ3 enables uptake of targeted fluorescent probes into ovarian cancer cells and tumors |journal=Bioorg. Med. Chem. |volume=26 |issue=8 |pages=2085–2091 |date=May 2018 |pmid=29548784 |pmc=5963687 |doi=10.1016/j.bmc.2018.03.007 |url=}}</ref>
+|
+* One of the most important mediator of angiogenesis
+* promotes smooth muscle cells migration and proliferation
+|
+* Promotes angiogenesis
+* Promotes survival
+|-
+|style="background:#DCDCDC;" align="center" + |Focal adhesion kinase (FAK)<ref name="pmid10436008">{{cite journal |vauthors=Shen Y, Schaller MD |title=Focal adhesion targeting: the critical determinant of FAK regulation and substrate phosphorylation |journal=Mol. Biol. Cell |volume=10 |issue=8 |pages=2507–18 |date=August 1999 |pmid=10436008 |pmc=25482 |doi=10.1091/mbc.10.8.2507 |url=}}</ref><ref name="pmid21118706">{{cite journal |vauthors=Zhao X, Guan JL |title=Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis |journal=Adv. Drug Deliv. Rev. |volume=63 |issue=8 |pages=610–5 |date=July 2011 |pmid=21118706 |pmc=3132829 |doi=10.1016/j.addr.2010.11.001 |url=}}</ref><ref name="pmid26622614">{{cite journal |vauthors=Li M, Hong LI, Liao M, Guo G |title=Expression and clinical significance of focal adhesion kinase and adrenomedullin in epithelial ovarian cancer |journal=Oncol Lett |volume=10 |issue=2 |pages=1003–1007 |date=August 2015 |pmid=26622614 |pmc=4508992 |doi=10.3892/ol.2015.3278 |url=}}</ref>
+|
+* Promotes endothelial cells migration
+* May play a role in integrin-dependent cell survival signal
+* Inhibits apoptosis
+* Enhances cell motility
+|
+* Promotes angiogenesis
+* Promotes tumor cells survival
+* Inhibits apoptosis
+* Promotes tumor metastasis
+|-
+|style="background:#DCDCDC;" align="center" + |E-cadherin<ref name="pmid22543706">{{cite journal |vauthors=Dong LL, Liu L, Ma CH, Li JS, Du C, Xu S, Han LH, Li L, Wang XW |title=E-cadherin promotes proliferation of human ovarian cancer cells in vitro via activating MEK/ERK pathway |journal=Acta Pharmacol. Sin. |volume=33 |issue=6 |pages=817–22 |date=June 2012 |pmid=22543706 |pmc=4010376 |doi=10.1038/aps.2012.30 |url=}}</ref><ref name="pmid14613514">{{cite journal |vauthors=Pećina-Slaus N |title=Tumor suppressor gene E-cadherin and its role in normal and malignant cells |journal=Cancer Cell Int. |volume=3 |issue=1 |pages=17 |date=October 2003 |pmid=14613514 |pmc=270068 |doi=10.1186/1475-2867-3-17 |url=}}</ref><ref name="pmid27582386">{{cite journal |vauthors=Petrova YI, Schecterson L, Gumbiner BM |title=Roles for E-cadherin cell surface regulation in cancer |journal=Mol. Biol. Cell |volume=27 |issue=21 |pages=3233–3244 |date=November 2016 |pmid=27582386 |pmc=5170857 |doi=10.1091/mbc.E16-01-0058 |url=}}</ref>
+|
+* One of the most important promoter of cell-cell adhesion
+* Play critical role in formation and maintenance of epithelia, and tissue formation
+|
+* Loss or mutations results in
+** epithelial–mesenchymal transition
+** decreased cell-cell adhesion
+** tumor cells invasion
+** metastasis
+|}
+=== Hereditary Epithelial Ovarian Carcinoma: An overview of Hereditary Syndromes and the Genetic Mutations ===
+==== Hereditary Breast and Ovarian Cancer (HBOC) ====
+* Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant disorder caused by mutations in BRCA1 and BRCA2 genes that are responsible for DNA repair in homologous recombination pathway.<ref name="pmid19383374">{{cite journal |vauthors=Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK |title=Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management |journal=Mol Oncol |volume=3 |issue=2 |pages=97–137 |date=April 2009 |pmid=19383374 |pmc=2778287 |doi=10.1016/j.molonc.2009.02.004 |url=}}</ref><ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+* Individuals with this disorder are at risk of developing breast (lifetime risk is 30-80%) and ovarian cancer (lifetime risk is 30-50%), along with other malignancies such as pancreatic, stomach, laryngeal, fallopian tube and prostate cancer.<ref name="pmid19383374">{{cite journal |vauthors=Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK |title=Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management |journal=Mol Oncol |volume=3 |issue=2 |pages=97–137 |date=April 2009 |pmid=19383374 |pmc=2778287 |doi=10.1016/j.molonc.2009.02.004 |url=}}</ref><ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref>
+* The reason for increased susceptibility to ovarian and epithelial cancer is not fully understood but but may be explained by repression of the transcription of hormone-mediated signalling factors or production of reactive oxygen species during menstrual cycle mediating DNA damage.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid10334989">{{cite journal |vauthors=Fan S, Wang J, Yuan R, Ma Y, Meng Q, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID, Rosen EM |title=BRCA1 inhibition of estrogen receptor signaling in transfected cells |journal=Science |volume=284 |issue=5418 |pages=1354–6 |date=May 1999 |pmid=10334989 |doi= |url=}}</ref><ref name="pmid11158190">{{cite journal |vauthors=Hamada J, Nakata D, Nakae D, Kobayashi Y, Akai H, Konishi Y, Okada F, Shibata T, Hosokawa M, Moriuchi T |title=Increased oxidative DNA damage in mammary tumor cells by continuous epidermal growth factor stimulation |journal=J. Natl. Cancer Inst. |volume=93 |issue=3 |pages=214–9 |date=February 2001 |pmid=11158190 |doi= |url=}}</ref>
+{| class="wikitable"
+|+
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Malignancies associated with BRCA mutations (Hereditary breast and ovarian cancer syndrome)<ref name="pmid26557407">{{cite journal |vauthors=Famorca-Tran J, Roux G |title=The Consequences of a BRCA Mutation in Women |journal=J Adv Pract Oncol |volume=6 |issue=3 |pages=194–210 |date=2015 |pmid=26557407 |pmc=4625626 |doi= |url=}}</ref>
+|-
+|
+* Breast cancer (male and female)
+* Ovarian cancer
+* Fallopian tube carcinoma
+* Primary papillary carcinoma of the peritoneum
+* Prostate cancer
+* Uterine body cancer
+* Cervical cancer
+* Pancreatic cancer
+* Gall bladder cancer
+* Bile duct cancer
+* Stomach cancer
+* Melanoma
+|}
+==== Lynch Syndrome ====
+* Lynch syndrome (LS), also known as hereditary nonpolyposis colon cancer (HNPCC), is characterized by germline mutations in DNA mismatch repair genes ''MLH1'', ''MSH2'', ''MSH6'', ''MLH3'', and ''PMS2.''<ref name="pmid19383374">{{cite journal |vauthors=Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK |title=Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management |journal=Mol Oncol |volume=3 |issue=2 |pages=97–137 |date=April 2009 |pmid=19383374 |doi=10.1016/j.molonc.2009.02.004 |url=}}</ref><ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid23572416">{{cite journal |vauthors=Martín-López JV, Fishel R |title=The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome |journal=Fam. Cancer |volume=12 |issue=2 |pages=159–68 |date=June 2013 |pmid=23572416 |pmc=4235668 |doi=10.1007/s10689-013-9635-x |url=}}</ref>
+* A simplified version of repair mechanism by mismatch repair genes products is described below:<ref name="pmid23572416">{{cite journal |vauthors=Martín-López JV, Fishel R |title=The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome |journal=Fam. Cancer |volume=12 |issue=2 |pages=159–68 |date=June 2013 |pmid=23572416 |pmc=4235668 |doi=10.1007/s10689-013-9635-x |url=}}</ref><ref name="pmid18406444">{{cite journal |vauthors=Hsieh P, Yamane K |title=DNA mismatch repair: molecular mechanism, cancer, and ageing |journal=Mech. Ageing Dev. |volume=129 |issue=7-8 |pages=391–407 |date=2008 |pmid=18406444 |pmc=2574955 |doi=10.1016/j.mad.2008.02.012 |url=}}</ref>
+'''MutS homologs (MSHs) recognize the DNA mismatch → MutS homologs (MSHs) recruit MutL homologs (''MLHs)'' → excision of mismatched DNA → DNA polymerase re-synthesizes DNA.'''
+* Accounted for 10-15% of all ovarian cancers, this syndrome is caused by inherited mutation in one allele and then loss of second allele (secondary hit).<ref name="pmid19383374">{{cite journal |vauthors=Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK |title=Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management |journal=Mol Oncol |volume=3 |issue=2 |pages=97–137 |date=April 2009 |pmid=19383374 |pmc=2778287 |doi=10.1016/j.molonc.2009.02.004 |url=}}</ref><ref name="pmid24978665">{{cite journal |vauthors=Sehgal R, Sheahan K, O'Connell PR, Hanly AM, Martin ST, Winter DC |title=Lynch syndrome: an updated review |journal=Genes (Basel) |volume=5 |issue=3 |pages=497–507 |date=June 2014 |pmid=24978665 |pmc=4198913 |doi=10.3390/genes5030497 |url=}}</ref>
+* The most common malignancies in Lynch syndrome are colorectal carcinoma and gynecological cancers, endometrial carcinoma being the most common among gynecological malignancies followed by ovarian carcinoma.<ref name="pmid24978665">{{cite journal |vauthors=Sehgal R, Sheahan K, O'Connell PR, Hanly AM, Martin ST, Winter DC |title=Lynch syndrome: an updated review |journal=Genes (Basel) |volume=5 |issue=3 |pages=497–507 |date=June 2014 |pmid=24978665 |pmc=4198913 |doi=10.3390/genes5030497 |url=}}</ref>
+* Other malignancies that have been observed in lynch syndrome are gastric cancer, small bowel malignancies, hepatobiliary epithelial carcinoma, uroepithelial epithelial carcinoma and brain tumors.<ref name="pmid24978665">{{cite journal |vauthors=Sehgal R, Sheahan K, O'Connell PR, Hanly AM, Martin ST, Winter DC |title=Lynch syndrome: an updated review |journal=Genes (Basel) |volume=5 |issue=3 |pages=497–507 |date=June 2014 |pmid=24978665 |pmc=4198913 |doi=10.3390/genes5030497 |url=}}</ref><ref name="pmid18809606">{{cite journal |vauthors=Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Clendenning M, Sotamaa K, Prior T, Westman JA, Panescu J, Fix D, Lockman J, LaJeunesse J, Comeras I, de la Chapelle A |title=Feasibility of screening for Lynch syndrome among patients with colorectal cancer |journal=J. Clin. Oncol. |volume=26 |issue=35 |pages=5783–8 |date=December 2008 |pmid=18809606 |pmc=2645108 |doi=10.1200/JCO.2008.17.5950 |url=}}</ref>
+[[File:Genetic variation in Lynch syndrome..png|alt=Genetic variation in Lynch syndrome.|center|frame|Genetic variation in Lynch syndrome.<ref name="pmid26873718">{{cite journal |vauthors=Peltomäki P |title=Update on Lynch syndrome genomics |journal=Fam. Cancer |volume=15 |issue=3 |pages=385–93 |date=July 2016 |pmid=26873718 |pmc=4901089 |doi=10.1007/s10689-016-9882-8 |url=}}</ref>]]
+==== Li-Fraumeni Syndrome ====
+* Li-Fraumeni Syndrome is an autosomal dominant disorder caused by germline mutation in TP53, the most mutated gene in human cancers. The most common of the mutations are missense mutations.<ref name="pmid260752292">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid28191499">{{cite journal |vauthors=Miller M, Shirole N, Tian R, Pal D, Sordella R |title=The Evolution of TP53 Mutations: From Loss-of-Function to Separation-of-Function Mutants |journal=J Cancer Biol Res |volume=4 |issue=4 |pages= |date=2016 |pmid=28191499 |pmc=5298884 |doi= |url=}}</ref>
+* TP53 encodes for a transcription factor that responds to various cell signals and is a major regulator of the cell cycle. It is involved in variety of cellular functions such as cellular proliferation and cell cycle, apoptosis, and stability & integrity of the genome.<ref name="pmid260752293">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid28191499">{{cite journal |vauthors=Miller M, Shirole N, Tian R, Pal D, Sordella R |title=The Evolution of TP53 Mutations: From Loss-of-Function to Separation-of-Function Mutants |journal=J Cancer Biol Res |volume=4 |issue=4 |pages= |date=2016 |pmid=28191499 |pmc=5298884 |doi= |url=}}</ref>
+* Mutations in TP53 resulting defective or decreased p53 are not only implicated in pathogenesis but also impact prognosis, causing worse survival rate among the individuals with the mutations.<ref name="pmid260752293">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid20142599">{{cite journal |vauthors=Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, Bouffet E, Malkin D, Hawkins C |title=Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations |journal=J. Clin. Oncol. |volume=28 |issue=8 |pages=1345–50 |date=March 2010 |pmid=20142599 |doi=10.1200/JCO.2009.23.5952 |url=}}</ref>
+* These mutations are most commonly observed in epithelial ovarian cancer (47%), colorectal carcinoma (43%), head/neck cancer (42%), and esophageal cancer (41%). Breast cancer, sarcoma and brain, and adrenocortical carcinoma account for majority of the tumors encountered in Li-Fraumeni syndrome.<ref name="pmid260752293">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid2046748">{{cite journal |vauthors=Levine AJ, Momand J, Finlay CA |title=The p53 tumour suppressor gene |journal=Nature |volume=351 |issue=6326 |pages=453–6 |date=June 1991 |pmid=2046748 |doi=10.1038/351453a0 |url=}}</ref>
+==== Site-Specific Ovarian Cancer ====
+* A term used to describe families in which there are several relatives with epithelial ovarian cancer but no other co-existent malignancies that are associated with other hereditary syndromes associated with epithelial ovarian cancer.<ref name="pmid20811826">{{cite journal |vauthors=Shulman LP, Dungan JS |title=Cancer genetics: risks and mechanisms of cancer in women with inherited susceptibility to epithelial ovarian cancer |journal=Cancer Treat. Res. |volume=156 |issue= |pages=69–85 |date=2010 |pmid=20811826 |pmc=3086477 |doi=10.1007/978-1-4419-6518-9_6 |url=}}</ref>
+* A hypothesis is that it is caused by gen/genes that are yet to be identified. Site-specific ovarian cancer appears to be transmitted in autosomal-dominant fashion in some families but some studies have suggested the risk to be as low as 5%.<ref name="pmid20811826">{{cite journal |vauthors=Shulman LP, Dungan JS |title=Cancer genetics: risks and mechanisms of cancer in women with inherited susceptibility to epithelial ovarian cancer |journal=Cancer Treat. Res. |volume=156 |issue= |pages=69–85 |date=2010 |pmid=20811826 |pmc=3086477 |doi=10.1007/978-1-4419-6518-9_6 |url=}}</ref><ref name="pmid9637117">{{cite journal |vauthors=Stratton JF, Pharoah P, Smith SK, Easton D, Ponder BA |title=A systematic review and meta-analysis of family history and risk of ovarian cancer |journal=Br J Obstet Gynaecol |volume=105 |issue=5 |pages=493–9 |date=May 1998 |pmid=9637117 |doi= |url=}}</ref>
+==== Cowden Syndrome ====
+* An autosomal-dominant syndrome , caused by mutations in PTEN gene, has been associated with a variety of neoplastic/non-neoplastic lesions and clinical manifestations throughout the body including:<ref name="pmid20811826">{{cite journal |vauthors=Shulman LP, Dungan JS |title=Cancer genetics: risks and mechanisms of cancer in women with inherited susceptibility to epithelial ovarian cancer |journal=Cancer Treat. Res. |volume=156 |issue= |pages=69–85 |date=2010 |pmid=20811826 |pmc=3086477 |doi=10.1007/978-1-4419-6518-9_6 |url=}}</ref><ref name="pmid17526800">{{cite journal |vauthors=Lachlan KL, Lucassen AM, Bunyan D, Temple IK |title=Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers |journal=J. Med. Genet. |volume=44 |issue=9 |pages=579–85 |date=September 2007 |pmid=17526800 |pmc=2597943 |doi=10.1136/jmg.2007.049981 |url=}}</ref><ref name="pmid233444092">{{cite journal |vauthors=Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P |title=Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer |journal=Obstet Gynecol |volume=121 |issue=2 Pt 2 Suppl 1 |pages=461–4 |date=February 2013 |pmid=23344409 |pmc=3799979 |doi=http://10 1097/AOG.0b013e318270444f |url=}}</ref>
+** Epithelial ovarian cancer
+** Hamartomatous lesions of skin and organs
+** Macrocephaly
+** Breast cancer
+** Thyroid cancer
+** Endometrial cancer
+==== ''RAD51'' ====
+* RAD51 is a recombinase that binds with eight BRC repeats of BRCA2. This allows RAD51 to be recruited to double stranded DNA breaks, an essential step in homologous recombination double stranded DNA repair.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid20729858">{{cite journal |vauthors=Thorslund T, McIlwraith MJ, Compton SA, Lekomtsev S, Petronczki M, Griffith JD, West SC |title=The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA |journal=Nat. Struct. Mol. Biol. |volume=17 |issue=10 |pages=1263–5 |date=October 2010 |pmid=20729858 |pmc=4041013 |doi=10.1038/nsmb.1905 |url=}}</ref><ref name="pmid19303847">{{cite journal |vauthors=Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK, Venkitaraman AR, Kowalczykowski SC |title=The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51 |journal=Cell |volume=136 |issue=6 |pages=1032–43 |date=March 2009 |pmid=19303847 |pmc=2669112 |doi=10.1016/j.cell.2009.02.019 |url=}}</ref><ref name="pmid260752292">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref>
+* Some studies have suggested risk for developing ovarian cancer in RAD51 mutations is as high as six-fold. There is also an increased risk for developing breast cancer.<ref name="pmid260752292">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid21822267">{{cite journal |vauthors=Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, Bowden G, Kalmyrzaev B, Warren-Perry M, Snape K, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Greenhalgh L, Henderson A, Izatt L, Kumar A, Lalloo F, Miedzybrodzka Z, Morrison PJ, Paterson J, Porteous M, Rogers MT, Shanley S, Walker L, Eccles D, Evans DG, Renwick A, Seal S, Lord CJ, Ashworth A, Reis-Filho JS, Antoniou AC, Rahman N |title=Germline mutations in RAD51D confer susceptibility to ovarian cancer |journal=Nat. Genet. |volume=43 |issue=9 |pages=879–882 |date=August 2011 |pmid=21822267 |pmc=4845885 |doi=10.1038/ng.893 |url=}}</ref><ref name="pmid20400964">{{cite journal |vauthors=Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H |title=Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene |journal=Nat. Genet. |volume=42 |issue=5 |pages=410–4 |date=May 2010 |pmid=20400964 |doi=10.1038/ng.569 |url=}}</ref>
+==== ''PALB2'' ====
+* Partner and localizer of BRCA2 (PALB2) physically connects BRCA1 and BRCA2 through N-terminal coiled-coil domain and the C terminus. This BRCA2 interacting protein plays an essential role in DNA repair.<ref name="pmid22193408">{{cite journal |vauthors=Roy R, Chun J, Powell SN |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nat. Rev. Cancer |volume=12 |issue=1 |pages=68–78 |date=December 2011 |pmid=22193408 |pmc=4972490 |doi=10.1038/nrc3181 |url=}}</ref><ref name="pmid19369211">{{cite journal |vauthors=Sy SM, Huen MS, Chen J |title=PALB2 is an integral component of the BRCA complex required for homologous recombination repair |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=106 |issue=17 |pages=7155–60 |date=April 2009 |pmid=19369211 |pmc=2678481 |doi=10.1073/pnas.0811159106 |url=}}</ref><ref name="pmid16793542">{{cite journal |vauthors=Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM |title=Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2 |journal=Mol. Cell |volume=22 |issue=6 |pages=719–29 |date=June 2006 |pmid=16793542 |doi=10.1016/j.molcel.2006.05.022 |url=}}</ref>
+* The association of PALB2 with ovarian cancer has not be fully established but an increased risk for breast cancer, pancreatic cancer and ovarian cancer has been observed in some studies.<ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid21285249">{{cite journal |vauthors=Casadei S, Norquist BM, Walsh T, Stray S, Mandell JB, Lee MK, Stamatoyannopoulos JA, King MC |title=Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer |journal=Cancer Res. |volume=71 |issue=6 |pages=2222–9 |date=March 2011 |pmid=21285249 |pmc=3059378 |doi=10.1158/0008-5472.CAN-10-3958 |url=}}</ref><ref name="pmid22505525">{{cite journal |vauthors=Poumpouridou N, Kroupis C |title=Hereditary breast cancer: beyond BRCA genetic analysis; PALB2 emerges |journal=Clin. Chem. Lab. Med. |volume=50 |issue=3 |pages=423–34 |date=December 2011 |pmid=22505525 |doi=10.1515/cclm-2011-0840 |url=}}</ref>
+==== ''CHEK2'' ====
+* CHEK2 gene encodes for a protein called checkpoint kinase 2 (CHK2). It interacts with other regulators and tumor suppressors such as TP53 to play a role in tumor suppression through cell-cycle regulation and apoptosis.<ref name="urlCHEK2 gene - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/gene/CHEK2 |title=CHEK2 gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid19782031">{{cite journal |vauthors=Cai Z, Chehab NH, Pavletich NP |title=Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase |journal=Mol. Cell |volume=35 |issue=6 |pages=818–29 |date=September 2009 |pmid=19782031 |doi=10.1016/j.molcel.2009.09.007 |url=}}</ref>
+* There are conflicting results regarding association of CHEK2 with ovarian cancers. Some studies have suggested no association but the limitations were observed because of focus on only certain allelic mutations in CHEK2.<ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid11967536">{{cite journal |vauthors=Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR |title=Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations |journal=Nat. Genet. |volume=31 |issue=1 |pages=55–9 |date=May 2002 |pmid=11967536 |doi=10.1038/ng879 |url=}}</ref>
+==== Mre11 Complex ====
+* Mre11 Complex is involved in DNA repair and comprises of meiotic recombination 11 (MRE11), RAD50 and Nijmegen breakage syndrome 1 (NBS1; also known as nibrin).<ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid21252998">{{cite journal |vauthors=Stracker TH, Petrini JH |title=The MRE11 complex: starting from the ends |journal=Nat. Rev. Mol. Cell Biol. |volume=12 |issue=2 |pages=90–103 |date=February 2011 |pmid=21252998 |pmc=3905242 |doi=10.1038/nrm3047 |url=}}</ref>
+* This complex plays an essential role in homologous recombination mediated DNA repair, non-homologous end-joining (NHEJ) and alternative non-homologous end-joining (A-NHEJ) pathways, all involved in double stranded DNA repair.<ref name="pmid21252998">{{cite journal |vauthors=Stracker TH, Petrini JH |title=The MRE11 complex: starting from the ends |journal=Nat. Rev. Mol. Cell Biol. |volume=12 |issue=2 |pages=90–103 |date=February 2011 |pmid=21252998 |pmc=3905242 |doi=10.1038/nrm3047 |url=}}</ref><ref name="pmid20655309">{{cite journal |vauthors=Lamarche BJ, Orazio NI, Weitzman MD |title=The MRN complex in double-strand break repair and telomere maintenance |journal=FEBS Lett. |volume=584 |issue=17 |pages=3682–95 |date=September 2010 |pmid=20655309 |pmc=2946096 |doi=10.1016/j.febslet.2010.07.029 |url=}}</ref>
+* Some studies have suggested an increased susceptibility to ovarian and breast cancers in hereditary mutations in Mre11 complex.<ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid14684699">{{cite journal |vauthors=Heikkinen K, Karppinen SM, Soini Y, Mäkinen M, Winqvist R |title=Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility |journal=J. Med. Genet. |volume=40 |issue=12 |pages=e131 |date=December 2003 |pmid=14684699 |pmc=1735331 |doi= |url=}}</ref>
+==== ''BARD1'' ====
+* This gene encodes for a peptide that interacts with BRCA1 and forms a heterodiamer that plays a role in homologous recombination mediated repair of double stranded DNA breaks.<ref name="pmid14560035">{{cite journal |vauthors=Westermark UK, Reyngold M, Olshen AB, Baer R, Jasin M, Moynahan ME |title=BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks |journal=Mol. Cell. Biol. |volume=23 |issue=21 |pages=7926–36 |date=November 2003 |pmid=14560035 |doi= |url=}}</ref><ref name="pmid11573085">{{cite journal |vauthors=Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE |title=Structure of a BRCA1-BARD1 heterodimeric RING-RING complex |journal=Nat. Struct. Biol. |volume=8 |issue=10 |pages=833–7 |date=October 2001 |pmid=11573085 |doi=10.1038/nsb1001-833 |url=}}</ref>
+* Mutations in BARD1 have been associated with breast and ovarian cancer.<ref name="pmid26075229">{{cite journal |vauthors=Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L |title=Hereditary ovarian cancer: not only BRCA 1 and 2 genes |journal=Biomed Res Int |volume=2015 |issue= |pages=341723 |date=2015 |pmid=26075229 |pmc=4449870 |doi=10.1155/2015/341723 |url=}}</ref><ref name="pmid25994375">{{cite journal |vauthors=Klonowska K, Ratajska M, Czubak K, Kuzniacka A, Brozek I, Koczkowska M, Sniadecki M, Debniak J, Wydra D, Balut M, Stukan M, Zmienko A, Nowakowska B, Irminger-Finger I, Limon J, Kozlowski P |title=Analysis of large mutations in BARD1 in patients with breast and/or ovarian cancer: the Polish population as an example |journal=Sci Rep |volume=5 |issue= |pages=10424 |date=May 2015 |pmid=25994375 |doi=10.1038/srep10424 |url=}}</ref>
+==== BRIP1 ====
+* BRCA1-interacting protein 1 (BRIP1) encodes for a helicase that interacts with BRCA1 in homologous recombination mediated repair of double stranded DNA breaks.<ref name="urlBRIP1 gene - Genetics Home Reference - NIH">{{cite web |url=++++https://ghr.nlm.nih.gov/gene/BRIP1 |title=BRIP1 gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid28411145">{{cite journal |vauthors=Ring KL, Garcia C, Thomas MH, Modesitt SC |title=Current and future role of genetic screening in gynecologic malignancies |journal=Am. J. Obstet. Gynecol. |volume=217 |issue=5 |pages=512–521 |date=November 2017 |pmid=28411145 |doi=10.1016/j.ajog.2017.04.011 |url=}}</ref>
+* Mutation in BRIP1 gene association with familial ovarian cancer have been demonstrated in some studies. There also been proposed risk for breast cancer but it has yet to be established.<ref name="pmid28411145">{{cite journal |vauthors=Ring KL, Garcia C, Thomas MH, Modesitt SC |title=Current and future role of genetic screening in gynecologic malignancies |journal=Am. J. Obstet. Gynecol. |volume=217 |issue=5 |pages=512–521 |date=November 2017 |pmid=28411145 |doi=10.1016/j.ajog.2017.04.011 |url=}}</ref><ref name="pmid29368626">{{cite journal |vauthors=Weber-Lassalle N, Hauke J, Ramser J, Richters L, Groß E, Blümcke B, Gehrig A, Kahlert AK, Müller CR, Hackmann K, Honisch E, Weber-Lassalle K, Niederacher D, Borde J, Thiele H, Ernst C, Altmüller J, Neidhardt G, Nürnberg P, Klaschik K, Schroeder C, Platzer K, Volk AE, Wang-Gohrke S, Just W, Auber B, Kubisch C, Schmidt G, Horvath J, Wappenschmidt B, Engel C, Arnold N, Dworniczak B, Rhiem K, Meindl A, Schmutzler RK, Hahnen E |title=BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer |journal=Breast Cancer Res. |volume=20 |issue=1 |pages=7 |date=January 2018 |pmid=29368626 |pmc=5784717 |doi=10.1186/s13058-018-0935-9 |url=}}</ref>
+=== An attempt to explain the origin of carcinogenesis in sporadic epithelial carcinoma ===
+{| class="wikitable"
+|+
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Proposed
+hypothesis
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Proposed
+Mechanism
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |For
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Against
+|-
+| style="background:#DCDCDC;" align="center" + | '''Incessant ovulation'''<ref name="pmid21761359">{{cite journal |vauthors=Saad AF, Hu W, Sood AK |title=Microenvironment and pathogenesis of epithelial ovarian cancer |journal=Horm Cancer |volume=1 |issue=6 |pages=277–90 |date=December 2010 |pmid=21761359 |pmc=3199131 |doi=10.1007/s12672-010-0054-2 |url=}}</ref><ref name="pmid12181107">{{cite journal |vauthors=Riman T, Dickman PW, Nilsson S, Correia N, Nordlinder H, Magnusson CM, Persson IR |title=Risk factors for invasive epithelial ovarian cancer: results from a Swedish case-control study |journal=Am. J. Epidemiol. |volume=156 |issue=4 |pages=363–73 |date=August 2002 |pmid=12181107 |doi= |url=}}</ref><ref name="pmid2348208">{{cite journal |vauthors=Gwinn ML, Lee NC, Rhodes PH, Layde PM, Rubin GL |title=Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer |journal=J Clin Epidemiol |volume=43 |issue=6 |pages=559–68 |date=1990 |pmid=2348208 |doi= |url=}}</ref><ref name="pmid6539067">{{cite journal |vauthors=Nasca PC, Greenwald P, Chorost S, Richart R, Caputo T |title=An epidemiologic case-control study of ovarian cancer and reproductive factors |journal=Am. J. Epidemiol. |volume=119 |issue=5 |pages=705–13 |date=May 1984 |pmid=6539067 |doi= |url=}}</ref><ref name="pmid9839517">{{cite journal |vauthors=Risch HA |title=Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone |journal=J. Natl. Cancer Inst. |volume=90 |issue=23 |pages=1774–86 |date=December 1998 |pmid=9839517 |doi= |url=}}</ref><ref name="pmid8841217">{{cite journal |vauthors=Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C |title=Epithelial ovarian cancer risk among women with polycystic ovary syndrome |journal=Obstet Gynecol |volume=88 |issue=4 Pt 1 |pages=554–9 |date=October 1996 |pmid=8841217 |doi= |url=}}</ref>
+|
+* Every ovulatory cycle leads to epithelial injury and resultant repairs make cells more susceptible to mutations
+|
+* Increased incidences of ovarian epithelial cancers in advanced age (increased number of cycles)
+* Factors that decrease ovulatory cycles such as oral contraceptive use, pregnancy and breast-feeding decrease the risk for ovarian epithelial cancer
+|
+* Progesterone only oral contraceptives do not inhibit ovulatory cycles but still decrease the risk for ovarian epithelial cancers
+* Polycystic ovarian syndrome (PCOS) decreases the number of ovulatory cycles but increases the risk for ovarian epithelial cancer.
+|-
+| style="background:#DCDCDC;" align="center" + | '''Gonadotropins'''<ref name="pmid21761359">{{cite journal |vauthors=Saad AF, Hu W, Sood AK |title=Microenvironment and pathogenesis of epithelial ovarian cancer |journal=Horm Cancer |volume=1 |issue=6 |pages=277–90 |date=December 2010 |pmid=21761359 |pmc=3199131 |doi=10.1007/s12672-010-0054-2 |url=}}</ref><ref name="pmid8841217">{{cite journal |vauthors=Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C |title=Epithelial ovarian cancer risk among women with polycystic ovary syndrome |journal=Obstet Gynecol |volume=88 |issue=4 Pt 1 |pages=554–9 |date=October 1996 |pmid=8841217 |doi= |url=}}</ref><ref name="pmid11994371">{{cite journal |vauthors=Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC |title=Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovarian surface epithelial cells |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=5 |pages=2245–53 |date=May 2002 |pmid=11994371 |doi=10.1210/jcem.87.5.8506 |url=}}</ref><ref name="pmid20392831">{{cite journal |vauthors=Lau MT, Wong AS, Leung PC |title=Gonadotropins induce tumor cell migration and invasion by increasing cyclooxygenases expression and prostaglandin E(2) production in human ovarian cancer cells |journal=Endocrinology |volume=151 |issue=7 |pages=2985–93 |date=July 2010 |pmid=20392831 |doi=10.1210/en.2009-1318 |url=}}</ref><ref name="pmid15531506">{{cite journal |vauthors=Choi JH, Choi KC, Auersperg N, Leung PC |title=Overexpression of follicle-stimulating hormone receptor activates oncogenic pathways in preneoplastic ovarian surface epithelial cells |journal=J. Clin. Endocrinol. Metab. |volume=89 |issue=11 |pages=5508–16 |date=November 2004 |pmid=15531506 |doi=10.1210/jc.2004-0044 |url=}}</ref><ref name="pmid10469746">{{cite journal |vauthors=Ness RB, Cottreau C |title=Possible role of ovarian epithelial inflammation in ovarian cancer |journal=J. Natl. Cancer Inst. |volume=91 |issue=17 |pages=1459–67 |date=September 1999 |pmid=10469746 |doi= |url=}}</ref><ref name="pmid10620446">{{cite journal |vauthors=Zheng W, Lu JJ, Luo F, Zheng Y, Feng Yj, Felix JC, Lauchlan SC, Pike MC |title=Ovarian epithelial tumor growth promotion by follicle-stimulating hormone and inhibition of the effect by luteinizing hormone |journal=Gynecol. Oncol. |volume=76 |issue=1 |pages=80–8 |date=January 2000 |pmid=10620446 |doi=10.1006/gyno.1999.5628 |url=}}</ref>
+|
+* Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and human chorionic gonadotropin stimulate ovarian epithelial cells proliferation
+* Resultant increased mitotic activity make cells more susceptible to mutations
+|
+* Higher incidences of epthelial ovarian cancers in women taking infertility drugs in some studies
+* Polycystic ovarian syndrome (PCOS) and infertility increase the risk for ovarian epithelial cancers
+* Progesterone only oral contraceptives decrease the risk for ovarian epithelial cancers
+* Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are shown to increase cell proliferation in some studies
+* Up-regulation of Cox-1 and Cox-2 and resultant increase in PGE2 by follicle-stimulating hormone (FSH) and luteinizing hormone (LH)  has been observed
+* Up-regulation of  potential oncogenes in vitro such as  EGFR, HER-2, and c-myc, cyclin G2, Meis-1, β-catenin, β-1 integrin, and IGF-1 by Follicle-stimulating hormone (FSH) receptor over-expression
+*
+|
+* Some studies suggest that infertility, rather than gonadotropin drugs treatment, increases the susceptibility to epithelial ovarian cancers
+* No concrete linkage of gonadotropins to malignant transformation of surface epithelial cells of ovaries
+* Proposed hypothesis of gonadotropin role in tumor cell growth and survival rather than origin
+|-
+| style="background:#DCDCDC;" align="center" + | '''Hormonal influence'''<ref name="pmid21761359">{{cite journal |vauthors=Saad AF, Hu W, Sood AK |title=Microenvironment and pathogenesis of epithelial ovarian cancer |journal=Horm Cancer |volume=1 |issue=6 |pages=277–90 |date=December 2010 |pmid=21761359 |pmc=3199131 |doi=10.1007/s12672-010-0054-2 |url=}}</ref><ref name="pmid9839517">{{cite journal |vauthors=Risch HA |title=Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone |journal=J. Natl. Cancer Inst. |volume=90 |issue=23 |pages=1774–86 |date=December 1998 |pmid=9839517 |doi= |url=}}</ref><ref name="pmid8841217">{{cite journal |vauthors=Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C |title=Epithelial ovarian cancer risk among women with polycystic ovary syndrome |journal=Obstet Gynecol |volume=88 |issue=4 Pt 1 |pages=554–9 |date=October 1996 |pmid=8841217 |doi= |url=}}</ref><ref name="pmid8166126">{{cite journal |vauthors=Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Lewis JL, Strom BL, Harlap S, Shapiro S |title=A case-control study of oral contraceptive use and invasive epithelial ovarian cancer |journal=Am. J. Epidemiol. |volume=139 |issue=7 |pages=654–61 |date=April 1994 |pmid=8166126 |doi= |url=}}</ref><ref name="pmid11953818">{{cite journal |vauthors=Edmondson RJ, Monaghan JM, Davies BR |title=The human ovarian surface epithelium is an androgen responsive tissue |journal=Br. J. Cancer |volume=86 |issue=6 |pages=879–85 |date=March 2002 |pmid=11953818 |pmc=2364138 |doi=10.1038/sj.bjc.6600154 |url=}}</ref><ref name="pmid16620055">{{cite journal |vauthors=Seeger H, Wallwiener D, Mueck AO |title=Is there a protective role of progestogens on the proliferation of human ovarian cancer cells in the presence of growth factors? |journal=Eur. J. Gynaecol. Oncol. |volume=27 |issue=2 |pages=139–41 |date=2006 |pmid=16620055 |doi= |url=}}</ref>
+|
+* Androgens confer greater risk to epithelial ovarian cancer while progesterone decreases the rik
+|
+* Conditions that result in androgenic excess such as  Polycystic ovarian syndrome (PCOS), hirsutism, and acne have been shown to increase the risk for epithelial ovarian cancer
+* Andorgens can stimulate cellular proliferation (androgens are are thought to be pre-dominant in ovarian inclusion cysts)
+* Progesterone only oral contraceptives decrease the risk for ovarian epithelial cancers, possibly through decreased androgens
+|
+* No concrete linkage of androgens to malignant transformation of surface epithelial cells of ovaries
+* No evidence of androgens and their precursors affecting cancer cells growth
+|-
+| style="background:#DCDCDC;" align="center" + | '''Inflammation'''<ref name="pmid21761359">{{cite journal |vauthors=Saad AF, Hu W, Sood AK |title=Microenvironment and pathogenesis of epithelial ovarian cancer |journal=Horm Cancer |volume=1 |issue=6 |pages=277–90 |date=December 2010 |pmid=21761359 |pmc=3199131 |doi=10.1007/s12672-010-0054-2 |url=}}</ref><ref name="pmid10469746">{{cite journal |vauthors=Ness RB, Cottreau C |title=Possible role of ovarian epithelial inflammation in ovarian cancer |journal=J. Natl. Cancer Inst. |volume=91 |issue=17 |pages=1459–67 |date=September 1999 |pmid=10469746 |doi= |url=}}</ref><ref name="pmid15254653">{{cite journal |vauthors=Altinoz MA, Korkmaz R |title=NF-kappaB, macrophage migration inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the acetaminophen- and NSAID-prevention of the ovarian cancer |journal=Neoplasma |volume=51 |issue=4 |pages=239–47 |date=2004 |pmid=15254653 |doi= |url=}}</ref><ref name="pmid9065120">{{cite journal |vauthors=Heller DS, Westhoff C, Gordon RE, Katz N |title=The relationship between perineal cosmetic talc usage and ovarian talc particle burden |journal=Am. J. Obstet. Gynecol. |volume=174 |issue=5 |pages=1507–10 |date=May 1996 |pmid=9065120 |doi= |url=}}</ref>
+|
+* Cytokines and inflammatory cells are involved in ovulation and repair and increase susceptibility to mutations and carcinogenesis
+|
+* Non-steroidal anti-inflammatory drugs (NSAIDS) and Aminosalicylic acid (ASA) are thought to decrease the risk for epithelial ovarian cancer
+* Chemicals that cause inflammation such as talc and asbestos are shown to be associated with an increased risk for epithelial ovarian cancer
+* Inflammatory pathways and mediators have been observed in tumor pathogenesis and tumor micro-environment
+*
+|
+* No established linkage between talc and asbestos with pathogenesis of epithelial ovarian cancers in animal studies
+|}
+=== Obesity: A Risk Factor for Epithelial Cancer ===
+* A British study comprising of 1.2 million women found that incidences of epithelial ovarian cancer were higher among women with BMI >30 as compared to women with normal BMI, with risk increasing with incremental increase in BMI. A meta-analysis conducted Olsen et al.also found an increase risk for epithelial ovarian cancer in obese women.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid17986716">{{cite journal |vauthors=Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D |title=Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study |journal=BMJ |volume=335 |issue=7630 |pages=1134 |date=December 2007 |pmid=17986716 |pmc=2099519 |doi=10.1136/bmj.39367.495995.AE |url=}}</ref><ref name="pmid17223544">{{cite journal |vauthors=Olsen CM, Green AC, Whiteman DC, Sadeghi S, Kolahdooz F, Webb PM |title=Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis |journal=Eur. J. Cancer |volume=43 |issue=4 |pages=690–709 |date=March 2007 |pmid=17223544 |doi=10.1016/j.ejca.2006.11.010 |url=}}</ref>
+* It has been hypothesized that waist to hip ratio provides a better risk determination for epithelial ovarian cancer because of more accuracy in assessing true visceral fat deposition but remains to be validated.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid18280327">{{cite journal |vauthors=Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M |title=Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies |journal=Lancet |volume=371 |issue=9612 |pages=569–78 |date=February 2008 |pmid=18280327 |doi=10.1016/S0140-6736(08)60269-X |url=}}</ref>
+* The time at which women develop obesity during their life may be a key factor for increased risk for epithelial ovarian cancer. Multiple studies indicate that increased BMI in adolescence and/or early adulthood may confer a greater risk for developing epithelial ovarian cancer.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid12522018">{{cite journal |vauthors=Lubin F, Chetrit A, Freedman LS, Alfandary E, Fishler Y, Nitzan H, Zultan A, Modan B |title=Body mass index at age 18 years and during adult life and ovarian cancer risk |journal=Am. J. Epidemiol. |volume=157 |issue=2 |pages=113–20 |date=January 2003 |pmid=12522018 |doi= |url=}}</ref><ref name="pmid12928351">{{cite journal |vauthors=Engeland A, Tretli S, Bjørge T |title=Height, body mass index, and ovarian cancer: a follow-up of 1.1 million Norwegian women |journal=J. Natl. Cancer Inst. |volume=95 |issue=16 |pages=1244–8 |date=August 2003 |pmid=12928351 |doi= |url=}}</ref>
+* Another study postulates that duration and severity of obesity is also associated with increased risk for epithelial ovarian cancer and few others postulate that association of obesity with epithelial ovarian cancer is greater in premenopausal women than post-menopausal.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid17986716">{{cite journal |vauthors=Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D |title=Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study |journal=BMJ |volume=335 |issue=7630 |pages=1134 |date=December 2007 |pmid=17986716 |pmc=2099519 |doi=10.1136/bmj.39367.495995.AE |url=}}</ref><ref name="pmid27529652">{{cite journal |vauthors=Arnold M, Jiang L, Stefanick ML, Johnson KC, Lane DS, LeBlanc ES, Prentice R, Rohan TE, Snively BM, Vitolins M, Zaslavsky O, Soerjomataram I, Anton-Culver H |title=Duration of Adulthood Overweight, Obesity, and Cancer Risk in the Women's Health Initiative: A Longitudinal Study from the United States |journal=PLoS Med. |volume=13 |issue=8 |pages=e1002081 |date=August 2016 |pmid=27529652 |pmc=4987008 |doi=10.1371/journal.pmed.1002081 |url=}}</ref>
+* Another meta-analysis demonstrated that obesity is associated with not only an increased risk for epithelial ovarian cancer but also with decrease in overall survival and ovarian-cancer specific survival. Another study also showed an increase in ovarian cancer- related mortality in obese women.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid22609763">{{cite journal |vauthors=Protani MM, Nagle CM, Webb PM |title=Obesity and ovarian cancer survival: a systematic review and meta-analysis |journal=Cancer Prev Res (Phila) |volume=5 |issue=7 |pages=901–10 |date=July 2012 |pmid=22609763 |doi=10.1158/1940-6207.CAPR-12-0048 |url=}}</ref><ref name="pmid26151456">{{cite journal |vauthors=Nagle CM, Dixon SC, Jensen A, Kjaer SK, Modugno F, deFazio A, Fereday S, Hung J, Johnatty SE, Fasching PA, Beckmann MW, Lambrechts D, Vergote I, Van Nieuwenhuysen E, Lambrechts S, Risch HA, Rossing MA, Doherty JA, Wicklund KG, Chang-Claude J, Goodman MT, Ness RB, Moysich K, Heitz F, du Bois A, Harter P, Schwaab I, Matsuo K, Hosono S, Goode EL, Vierkant RA, Larson MC, Fridley BL, Høgdall C, Schildkraut JM, Weber RP, Cramer DW, Terry KL, Bandera EV, Paddock L, Rodriguez-Rodriguez L, Wentzensen N, Yang HP, Brinton LA, Lissowska J, Høgdall E, Lundvall L, Whittemore A, McGuire V, Sieh W, Rothstein J, Sutphen R, Anton-Culver H, Ziogas A, Pearce CL, Wu AH, Webb PM |title=Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium |journal=Br. J. Cancer |volume=113 |issue=5 |pages=817–26 |date=September 2015 |pmid=26151456 |pmc=4559823 |doi=10.1038/bjc.2015.245 |url=}}</ref>
+=== Diabetes Mellitus and The Risk of Epithelial Ovarian Cancer ===
+* While conflicting data is present for association of diabetes mellitus and an increased risk for epithelial ovarian cancer, multiple studies, however,  demonstrated diabetes as an independent risk factor for increased mortality in epithelial ovarian cancer.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid23354371">{{cite journal |vauthors=Lee JY, Jeon I, Kim JW, Song YS, Yoon JM, Park SM |title=Diabetes mellitus and ovarian cancer risk: a systematic review and meta-analysis of observational studies |journal=Int. J. Gynecol. Cancer |volume=23 |issue=3 |pages=402–12 |date=March 2013 |pmid=23354371 |doi=10.1097/IGC.0b013e31828189b2 |url=}}</ref><ref name="pmid26338721">{{cite journal |vauthors=Vrachnis N, Iavazzo C, Iliodromiti Z, Sifakis S, Alexandrou A, Siristatidis C, Grigoriadis C, Botsis D, Creatsas G |title=Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives |journal=Arch. Gynecol. Obstet. |volume=293 |issue=2 |pages=239–46 |date=February 2016 |pmid=26338721 |doi=10.1007/s00404-015-3858-z |url=}}</ref><ref name="pmid25014539">{{cite journal |vauthors=Chen HF, Chang YH, Ko MC, Li CY |title=A large scale population-based cohort study on the risk of ovarian neoplasm in patients with type 2 diabetes mellitus |journal=Gynecol. Oncol. |volume=134 |issue=3 |pages=576–80 |date=September 2014 |pmid=25014539 |doi=10.1016/j.ygyno.2014.07.001 |url=}}</ref><ref name="pmid21236474">{{cite journal |vauthors=Bakhru A, Buckanovich RJ, Griggs JJ |title=The impact of diabetes on survival in women with ovarian cancer |journal=Gynecol. Oncol. |volume=121 |issue=1 |pages=106–11 |date=April 2011 |pmid=21236474 |doi=10.1016/j.ygyno.2010.12.329 |url=}}</ref>
+* Findings in some studies indicate a greater risk for epithelial ovarian cancer in diabetic women while some suggest an increased risk only in pre-menopausal women, and some suggest no increase in risk for epithelial ovarian cancer at all.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid23354371">{{cite journal |vauthors=Lee JY, Jeon I, Kim JW, Song YS, Yoon JM, Park SM |title=Diabetes mellitus and ovarian cancer risk: a systematic review and meta-analysis of observational studies |journal=Int. J. Gynecol. Cancer |volume=23 |issue=3 |pages=402–12 |date=March 2013 |pmid=23354371 |doi=10.1097/IGC.0b013e31828189b2 |url=}}</ref><ref name="pmid26338721">{{cite journal |vauthors=Vrachnis N, Iavazzo C, Iliodromiti Z, Sifakis S, Alexandrou A, Siristatidis C, Grigoriadis C, Botsis D, Creatsas G |title=Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives |journal=Arch. Gynecol. Obstet. |volume=293 |issue=2 |pages=239–46 |date=February 2016 |pmid=26338721 |doi=10.1007/s00404-015-3858-z |url=}}</ref><ref name="pmid25014539">{{cite journal |vauthors=Chen HF, Chang YH, Ko MC, Li CY |title=A large scale population-based cohort study on the risk of ovarian neoplasm in patients with type 2 diabetes mellitus |journal=Gynecol. Oncol. |volume=134 |issue=3 |pages=576–80 |date=September 2014 |pmid=25014539 |doi=10.1016/j.ygyno.2014.07.001 |url=}}</ref>
+=== Metabolic Syndrome and the Risk of Epithelial Ovarian Cancer ===
+* The case for metabolic syndrome to be associated with an increased risk for epithelial ovarian cancer is similar to that of diabetes mellitus. There has been a fewer studies on association between metabolic syndrome and epithelial ovarian cancer and the results are conflicting with some found an increased risk for epithelial ovarian cancer in women with metabolic syndrome while some found no association.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid23093685">{{cite journal |vauthors=Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D |title=Metabolic syndrome and risk of cancer: a systematic review and meta-analysis |journal=Diabetes Care |volume=35 |issue=11 |pages=2402–11 |date=November 2012 |pmid=23093685 |pmc=3476894 |doi=10.2337/dc12-0336 |url=}}</ref><ref name="pmid21984693">{{cite journal |vauthors=Bjørge T, Lukanova A, Tretli S, Manjer J, Ulmer H, Stocks T, Selmer R, Nagel G, Almquist M, Concin H, Hallmans G, Jonsson H, Häggström C, Stattin P, Engeland A |title=Metabolic risk factors and ovarian cancer in the Metabolic Syndrome and Cancer project |journal=Int J Epidemiol |volume=40 |issue=6 |pages=1667–77 |date=December 2011 |pmid=21984693 |doi=10.1093/ije/dyr130 |url=}}</ref>
+* But an association of metabolic syndrome with increased ovarian cancer-related mortality was found in these studies. These studies however had limitation of lack of racial diversity because the study sample comprised only of Caucasian women.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid21984693">{{cite journal |vauthors=Bjørge T, Lukanova A, Tretli S, Manjer J, Ulmer H, Stocks T, Selmer R, Nagel G, Almquist M, Concin H, Hallmans G, Jonsson H, Häggström C, Stattin P, Engeland A |title=Metabolic risk factors and ovarian cancer in the Metabolic Syndrome and Cancer project |journal=Int J Epidemiol |volume=40 |issue=6 |pages=1667–77 |date=December 2011 |pmid=21984693 |doi=10.1093/ije/dyr130 |url=}}</ref>
+=== Pathogenesis of Epithelial Ovarian Cancer Associated with Metabolic Abnormalities ===
+* The work on mechanisms linking metabolic abnormalities to epithelial ovarian cancer is not yet complete and the way by which these abnormalities confer a greater risk for epithelial ovarian cancer is not well-understood but several theories have been put forward.
+* The most significant of these theories include role of cytokines and adipokines, immune cells, and aberrant signaling pathways in association with increased risk for epithelial ovarian cancer in women with metabolic derangement.
+==== Cytokines and Adipokines ====
+{| class="wikitable"
+|+
+! colspan="3" style="background:#4479BA; color: #FFFFFF;" align="center" + |The role of cytokines and adipokines in epithelial ovarian cancer
+|-
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Cytokines and adipokines
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Association with metabolic abnormalities
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Proposed mechanism in initiation and progression of epithelial ovarian cancer
+|-
+|style="background:#DCDCDC;" align="center" + |Tissue necrosis factor-α<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid16889756">{{cite journal |vauthors=Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G |title=Inflammation and cancer: how hot is the link? |journal=Biochem. Pharmacol. |volume=72 |issue=11 |pages=1605–21 |date=November 2006 |pmid=16889756 |doi=10.1016/j.bcp.2006.06.029 |url=}}</ref><ref name="pmid8387543">{{cite journal |vauthors=Naylor MS, Stamp GW, Foulkes WD, Eccles D, Balkwill FR |title=Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression |journal=J. Clin. Invest. |volume=91 |issue=5 |pages=2194–206 |date=May 1993 |pmid=8387543 |pmc=288222 |doi=10.1172/JCI116446 |url=}}</ref><ref name="pmid21912508">{{cite journal |vauthors=Braun S, Bitton-Worms K, LeRoith D |title=The link between the metabolic syndrome and cancer |journal=Int. J. Biol. Sci. |volume=7 |issue=7 |pages=1003–15 |date=2011 |pmid=21912508 |pmc=3164150 |doi= |url=}}</ref>
+|
+* Produced by immune cells (macrophages), tumor cells and fat cells
+* Shown to be elevated in obesity and diabetes mellitus
+|
+* Promotes matrix metalloproteinases that contribute to carcinognesis and increased risk for tumor cell invasion and metastasis
+* Promotes tumor cells growth by acting as paracrine and autocrine growth factor
+* Promotes angiogenesis that contribute to tumor progression
+* Promotes cell survival
+* Promotes cell proliferation
+* Inhibits apoptosis
+* Acts to decrease adiponectin levels by decreasing its production
+* Promotes aromatase expression in adipose tissues
+* Promotes insulin resistance
+* Promotes inflammation
+* A positive correlation of tissue necrosis factor-α levels with tumor grade of epithelial ovarian cancer
+* Elevated levels shown to be associated with decreased overall survival
+|-
+|style="background:#DCDCDC;" align="center" + |Leptin<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid24935119">{{cite journal |vauthors=Park J, Morley TS, Kim M, Clegg DJ, Scherer PE |title=Obesity and cancer--mechanisms underlying tumour progression and recurrence |journal=Nat Rev Endocrinol |volume=10 |issue=8 |pages=455–465 |date=August 2014 |pmid=24935119 |pmc=4374431 |doi=10.1038/nrendo.2014.94 |url=}}</ref><ref name="pmid19765303">{{cite journal |vauthors=Uddin S, Bu R, Ahmed M, Abubaker J, Al-Dayel F, Bavi P, Al-Kuraya KS |title=Overexpression of leptin receptor predicts an unfavorable outcome in Middle Eastern ovarian cancer |journal=Mol. Cancer |volume=8 |issue= |pages=74 |date=September 2009 |pmid=19765303 |pmc=2754986 |doi=10.1186/1476-4598-8-74 |url=}}</ref><ref name="pmid23354006">{{cite journal |vauthors=Chen C, Chang YC, Lan MS, Breslin M |title=Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways |journal=Int. J. Oncol. |volume=42 |issue=3 |pages=1113–9 |date=March 2013 |pmid=23354006 |doi=10.3892/ijo.2013.1789 |url=}}</ref><ref name="pmid26053184">{{cite journal |vauthors=Kato S, Abarzua-Catalan L, Trigo C, Delpiano A, Sanhueza C, García K, Ibañez C, Hormazábal K, Diaz D, Brañes J, Castellón E, Bravo E, Owen G, Cuello MA |title=Leptin stimulates migration and invasion and maintains cancer stem-like properties in ovarian cancer cells: an explanation for poor outcomes in obese women |journal=Oncotarget |volume=6 |issue=25 |pages=21100–19 |date=August 2015 |pmid=26053184 |pmc=4673253 |doi=10.18632/oncotarget.4228 |url=}}</ref>
+|
+* Produced by adipocytes
+* Shown to be elevated in obesity and produced by tumor cells
+* Leptin receptors expressed by tumor cells
+|
+* Inhibits natural killer function by decreasing
+** toxicity towards tumor cells
+** perforin production
+** interferon-γ secretion
+* Promotes secretion of interleukin-6 and tissue necrosis factor-α by monocytes
+* Promotes tumor cells growth and invasion
+* Promotes resistance to apoptosis
+* Promotes tumor cells proliferation
+* Promotes expression of cyclin-D that increases tumor cells growth and survival
+* Promotes tumor cells migration
+* Shown to decrease progression-free survival in epithelial ovarian tumors
+|-
+|style="background:#DCDCDC;" align="center" + |IL-6<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid23354006">{{cite journal |vauthors=Chen C, Chang YC, Lan MS, Breslin M |title=Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways |journal=Int. J. Oncol. |volume=42 |issue=3 |pages=1113–9 |date=March 2013 |pmid=23354006 |doi=10.3892/ijo.2013.1789 |url=}}</ref><ref name="pmid21340762">{{cite journal |vauthors=Gastl G, Plante M |title=Bioactive interleukin-6 levels in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer |journal=Methods Mol. Med. |volume=39 |issue= |pages=121–3 |date=2001 |pmid=21340762 |doi=10.1385/1-59259-071-3:121 |url=}}</ref>
+|
+* Produced by immune cells (macrophages), tumor cells and fat cells
+* Shown to be elevated in obesity and diabetes mellitus
+* Reactive oxygen species associated with an increased level of interlekin-6
+|
+* Promotes angiogenesis
+* Associated with increased aromatase that leads to elevated levels of estrogen
+* Inhibits apoptosis by increasing expression of anti-apoptotic proteins
+* Promotes resistance to chemotherapy
+* Promotes inflammation
+* Associated with increased levels of C-reactive protein
+* Response prediction to bevacizumab therapy
+*
+|-
+|style="background:#DCDCDC;" align="center" + |C reactive protein (CRP)<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid21912508">{{cite journal |vauthors=Braun S, Bitton-Worms K, LeRoith D |title=The link between the metabolic syndrome and cancer |journal=Int. J. Biol. Sci. |volume=7 |issue=7 |pages=1003–15 |date=2011 |pmid=21912508 |pmc=3164150 |doi= |url=}}</ref>
+|
+* Produced by liver
+* Shown to be elevated in obesity and diabetes mellitus
+|
+* Shown to be associated with an increased risk for developing epithelial ovarian cancer
+|-
+|style="background:#DCDCDC;" align="center" + |Monocyte chemotactic protein-1 (MCP-1)<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid24935119">{{cite journal |vauthors=Park J, Morley TS, Kim M, Clegg DJ, Scherer PE |title=Obesity and cancer--mechanisms underlying tumour progression and recurrence |journal=Nat Rev Endocrinol |volume=10 |issue=8 |pages=455–465 |date=August 2014 |pmid=24935119 |pmc=4374431 |doi=10.1038/nrendo.2014.94 |url=}}</ref><ref name="pmid24936477">{{cite journal |vauthors=Colvin EK |title=Tumor-associated macrophages contribute to tumor progression in ovarian cancer |journal=Front Oncol |volume=4 |issue= |pages=137 |date=2014 |pmid=24936477 |pmc=4047518 |doi=10.3389/fonc.2014.00137 |url=}}</ref>
+|
+* Produced by ovarian tumor cells
+* Induced by hypoxia inducible factor (levels elevated in obesity)
+* Elevated levels observed in obesity
+|
+* Promotes monocytes recruitment
+* Associated with increased density of tumor associated macrophages
+* May play a role in angiogenesis
+|-
+|style="background:#DCDCDC;" align="center" + |Adiponectin<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref><ref name="pmid18280327">{{cite journal |vauthors=Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M |title=Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies |journal=Lancet |volume=371 |issue=9612 |pages=569–78 |date=February 2008 |pmid=18280327 |doi=10.1016/S0140-6736(08)60269-X |url=}}</ref><ref name="pmid25456095">{{cite journal |vauthors=Mendonça FM, de Sousa FR, Barbosa AL, Martins SC, Araújo RL, Soares R, Abreu C |title=Metabolic syndrome and risk of cancer: which link? |journal=Metab. Clin. Exp. |volume=64 |issue=2 |pages=182–9 |date=February 2015 |pmid=25456095 |doi=10.1016/j.metabol.2014.10.008 |url=}}</ref><ref name="pmid23402904">{{cite journal |vauthors=Diaz ES, Karlan BY, Li AJ |title=Obesity-associated adipokines correlate with survival in epithelial ovarian cancer |journal=Gynecol. Oncol. |volume=129 |issue=2 |pages=353–7 |date=May 2013 |pmid=23402904 |doi=10.1016/j.ygyno.2013.02.006 |url=}}</ref>
+|
+* Produced by mature fat cells
+* Shown to be decreased in obesity and diabetes mellitus
+|
+* Anti-tumor effects lost/decreased in obesity and diabetes mellitus that include
+* insulin sensitivity
+* Inhibition of inflammation
+* inhibition of tumor growth
+* inhibition of angiogenesis
+* inhibition of tissue necrosis factor-α signaling
+|}
+==== Immune Cells ====
+* Immune cells may have a pro or anti-tumor effect, depending on the cell type. Metabolic risk factors may alter these cell types and their functions to have a promoter effect in initiation and progression of epithelial ovarian tumors.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref>
+* The table below provides a short overview of possible role of immune cells in pathogenesis of epithelial ovarian tumors.<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref>
+{| class="wikitable"
+|+
+! colspan="3" style="background:#4479BA; color: #FFFFFF;" align="center" + |The role of immune cells in epithelial ovarian cancer
+|-
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Cell type
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Link with metabolic risk factors
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Possible role in pathogenesis
+|-
+|style="background:#DCDCDC;" align="center" + |Dendritic cells<ref name="pmid25897374">{{cite journal |vauthors=Coosemans A, Baert T, Vergote I |title=A view on dendritic cell immunotherapy in ovarian cancer: how far have we come? |journal=Facts Views Vis Obgyn |volume=7 |issue=1 |pages=73–8 |date=2015 |pmid=25897374 |pmc=4402447 |doi= |url=}}</ref><ref name="pmid24501688">{{cite journal |vauthors=Coosemans A, Vergote I, Van Gool SW |title=Dendritic cell-based immunotherapy in ovarian cancer |journal=Oncoimmunology |volume=2 |issue=12 |pages=e27059 |date=December 2013 |pmid=24501688 |pmc=3913669 |doi=10.4161/onci.27059 |url=}}</ref><ref name="pmid30345421">{{cite journal |vauthors=Morehead LC, Cannon MJ |title=Further clinical advancement of dendritic cell vaccination against ovarian cancer |journal=Ann Res Hosp |volume=2 |issue= |pages= |date=August 2018 |pmid=30345421 |pmc=6192055 |doi=10.21037/arh.2018.08.02 |url=}}</ref>
+|
+* Tumor stroma-derived factor 1 (SDF-1) recruits dendritic cells
+|
+* Interleukin 10 by tumor cells leads to alteration in dendritic cells differentiation
+* These specific subtypes induced by tumor cells cytokines are less efficient in T-cells activation
+* Interact with programmed death-ligand 1 (PD-L1) to decrease T-cells effector function
+|-
+|style="background:#DCDCDC;" align="center" + |Macrophages<ref name="pmid24936477">{{cite journal |vauthors=Colvin EK |title=Tumor-associated macrophages contribute to tumor progression in ovarian cancer |journal=Front Oncol |volume=4 |issue= |pages=137 |date=2014 |pmid=24936477 |pmc=4047518 |doi=10.3389/fonc.2014.00137 |url=}}</ref><ref name="pmid15322536">{{cite journal |vauthors=Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W |title=Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival |journal=Nat. Med. |volume=10 |issue=9 |pages=942–9 |date=September 2004 |pmid=15322536 |doi=10.1038/nm1093 |url=}}</ref><ref name="pmid25781614">{{cite journal |vauthors=Schmidt FM, Weschenfelder J, Sander C, Minkwitz J, Thormann J, Chittka T, Mergl R, Kirkby KC, Faßhauer M, Stumvoll M, Holdt LM, Teupser D, Hegerl U, Himmerich H |title=Inflammatory cytokines in general and central obesity and modulating effects of physical activity |journal=PLoS ONE |volume=10 |issue=3 |pages=e0121971 |date=2015 |pmid=25781614 |pmc=4363366 |doi=10.1371/journal.pone.0121971 |url=}}</ref><ref name="pmid24507759">{{cite journal |vauthors=Zhang M, He Y, Sun X, Li Q, Wang W, Zhao A, Di W |title=A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients |journal=J Ovarian Res |volume=7 |issue= |pages=19 |date=February 2014 |pmid=24507759 |pmc=3939626 |doi=10.1186/1757-2215-7-19 |url=}}</ref><ref name="pmid26573796">{{cite journal |vauthors=Liu Y, Metzinger MN, Lewellen KA, Cripps SN, Carey KD, Harper EI, Shi Z, Tarwater L, Grisoli A, Lee E, Slusarz A, Yang J, Loughran EA, Conley K, Johnson JJ, Klymenko Y, Bruney L, Liang Z, Dovichi NJ, Cheatham B, Leevy WM, Stack MS |title=Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages |journal=Cancer Res. |volume=75 |issue=23 |pages=5046–57 |date=December 2015 |pmid=26573796 |pmc=4668203 |doi=10.1158/0008-5472.CAN-15-0706 |url=}}</ref>
+|
+* Two populations:
+** (1) M1 → classically activated tumor associated macrophages
+** (2) M2 → alternatively activated tumor associated macrophages
+* Studies indicate decreased M1 subpopulation in obese patients leading to ↓ M1/M2 ratio
+* Interferon gamma induce differentiation of macrophages into M1 subpopulation
+* Differentiation of macrophages into M2 subpopulation is possibly promoted by
+** transforming growth factor-beta
+** interleukin-4
+** interleukin-10
+** interleukin-13
+** colony stimulating factor-1
+|
+* M1
+** inhibit tumor progression
+** promote inflammation through production of cytokines
+** cytotoxic to tumor cell
+** produce and release reactive oxygen species (ROS)
+* M2
+** promote tumor cells growth
+** promote angiogenesis
+** promote invasion and metastasis
+** promote tissue repair
+** inhibits immune system
+** produce C-C motif chemokine 22 (CCL22)
+*
+|-
+|style="background:#DCDCDC;" align="center" + |Natural killer cells<ref name="pmid21463194">{{cite journal |vauthors=Preston CC, Goode EL, Hartmann LC, Kalli KR, Knutson KL |title=Immunity and immune suppression in human ovarian cancer |journal=Immunotherapy |volume=3 |issue=4 |pages=539–56 |date=April 2011 |pmid=21463194 |pmc=3147144 |doi=10.2217/imt.11.20 |url=}}</ref><ref name="pmid26776093">{{cite journal |vauthors=Naylor C, Petri WA |title=Leptin Regulation of Immune Responses |journal=Trends Mol Med |volume=22 |issue=2 |pages=88–98 |date=February 2016 |pmid=26776093 |doi=10.1016/j.molmed.2015.12.001 |url=}}</ref>
+|
+* Leptin may inhibit cytotoxic activity and interferon-γ production by natural killer cells
+* Mucin 16, Cell Surface Associated (MUC16) suppresses natural killer cells function
+|
+* Increased natural killer cells activity in peripheral blood → increased progression free survival
+* Higher number of natural killer cells in peritoneal/pleural fluids → poor prognosis
+|-
+|style="background:#DCDCDC;" align="center" + |B-cells<ref name="pmid26573796">{{cite journal |vauthors=Liu Y, Metzinger MN, Lewellen KA, Cripps SN, Carey KD, Harper EI, Shi Z, Tarwater L, Grisoli A, Lee E, Slusarz A, Yang J, Loughran EA, Conley K, Johnson JJ, Klymenko Y, Bruney L, Liang Z, Dovichi NJ, Cheatham B, Leevy WM, Stack MS |title=Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages |journal=Cancer Res. |volume=75 |issue=23 |pages=5046–57 |date=December 2015 |pmid=26573796 |pmc=4668203 |doi=10.1158/0008-5472.CAN-15-0706 |url=}}</ref><ref name="pmid23326565">{{cite journal |vauthors=Yang C, Lee H, Jove V, Deng J, Zhang W, Liu X, Forman S, Dellinger TH, Wakabayashi M, Yu H, Pal S |title=Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer |journal=PLoS ONE |volume=8 |issue=1 |pages=e54029 |date=2013 |pmid=23326565 |pmc=3542323 |doi=10.1371/journal.pone.0054029 |url=}}</ref><ref name="pmid16613351">{{cite journal |vauthors=Dong HP, Elstrand MB, Holth A, Silins I, Berner A, Trope CG, Davidson B, Risberg B |title=NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma |journal=Am. J. Clin. Pathol. |volume=125 |issue=3 |pages=451–8 |date=March 2006 |pmid=16613351 |doi= |url=}}</ref>
+|
+* Animal model studies indicate an up to threefold increase in B cells population in tumor cells in obese patients
+|
+* Higher B cells tumor population associated with poorer prognosis
+* Promote angiogenesis
+|-
+|style="background:#DCDCDC;" align="center" + |T-cells<ref name="pmid21463194">{{cite journal |vauthors=Preston CC, Goode EL, Hartmann LC, Kalli KR, Knutson KL |title=Immunity and immune suppression in human ovarian cancer |journal=Immunotherapy |volume=3 |issue=4 |pages=539–56 |date=April 2011 |pmid=21463194 |pmc=3147144 |doi=10.2217/imt.11.20 |url=}}</ref><ref name="pmid22040834">{{cite journal |vauthors=Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G |title=Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis |journal=Gynecol. Oncol. |volume=124 |issue=2 |pages=192–8 |date=February 2012 |pmid=22040834 |pmc=3298445 |doi=10.1016/j.ygyno.2011.09.039 |url=}}</ref><ref name="pmid16344461">{{cite journal |vauthors=Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K |title=Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue=51 |pages=18538–43 |date=December 2005 |pmid=16344461 |pmc=1311741 |doi=10.1073/pnas.0509182102 |url=}}</ref><ref name="pmid12529460">{{cite journal |vauthors=Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G |title=Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer |journal=N. Engl. J. Med. |volume=348 |issue=3 |pages=203–13 |date=January 2003 |pmid=12529460 |doi=10.1056/NEJMoa020177 |url=}}</ref>
+|
+* Interaction with programmed death-ligand 1 (PD-L1) inhibits CD4+ and CD8+ cells function
+* Transforming growth factor-β inhibits cytotoxic function of CD8+ cells
+* C-C motif chemokine 22 (CCL22) recruits regulatory T cells to the tumor
+|
+* CD4+ cells
+** produce interleukin-17 that may have an anti-tumor role
+* CD8+ cells
+** increased number is associated with increased survival
+* Regulatory T-cells
+** release interleukin-10 and transforming growth factor-β that inhibit anti-tumor function of T-cells
+** inhibit cytotoxic function of CD8+ T cells
+*
+|}
+*
+*
+==== Hormones, Signaling Pathways in Pathogenesis of Epithelial Ovarian Cancer and Their Link to Metabolic Risk Factors ====
+* Hormones and signaling pathways that may play a role in pathogenesis of epithelial ovarian cancer with link to metabolic abnormalities are summarized below in table:<ref name="pmid27751590">{{cite journal |vauthors=Craig ER, Londoño AI, Norian LA, Arend RC |title=Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review |journal=Gynecol. Oncol. |volume=143 |issue=3 |pages=674–683 |date=December 2016 |pmid=27751590 |pmc=5689410 |doi=10.1016/j.ygyno.2016.10.005 |url=}}</ref>
+{| class="wikitable"
+|+
+! colspan="3" style="background:#4479BA; color: #FFFFFF;" align="center" + |Possible role of hormones and signal transduction pathways in relation to metabolic abnormalities
+|-
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Hormone
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Link with metabolic risk factors
+!style="background:#4479BA; color: #FFFFFF;" align="center" + |Possible role in pathogenesis
+|-
+|style="background:#DCDCDC;" align="center" + |Hypoxia inducible factor (HIF)<ref name="pmid24935119">{{cite journal |vauthors=Park J, Morley TS, Kim M, Clegg DJ, Scherer PE |title=Obesity and cancer--mechanisms underlying tumour progression and recurrence |journal=Nat Rev Endocrinol |volume=10 |issue=8 |pages=455–465 |date=August 2014 |pmid=24935119 |pmc=4374431 |doi=10.1038/nrendo.2014.94 |url=}}</ref><ref name="pmid16889756">{{cite journal |vauthors=Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G |title=Inflammation and cancer: how hot is the link? |journal=Biochem. Pharmacol. |volume=72 |issue=11 |pages=1605–21 |date=November 2006 |pmid=16889756 |doi=10.1016/j.bcp.2006.06.029 |url=}}</ref><ref name="pmid26849037">{{cite journal |vauthors=Hansen JM, Coleman RL, Sood AK |title=Targeting the tumour microenvironment in ovarian cancer |journal=Eur. J. Cancer |volume=56 |issue= |pages=131–143 |date=March 2016 |pmid=26849037 |pmc=4769921 |doi=10.1016/j.ejca.2015.12.016 |url=}}</ref><ref name="pmid17609976">{{cite journal |vauthors=Wang B, Wood IS, Trayhurn P |title=Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes |journal=Pflugers Arch. |volume=455 |issue=3 |pages=479–92 |date=December 2007 |pmid=17609976 |pmc=2040175 |doi=10.1007/s00424-007-0301-8 |url=}}</ref>
+|
+* Increased in obesity due to relative hypoxia
+|
+* Promotes growth and survival by increased production/expression of
+** interleukin-6
+** tissue necrosis factor
+** monocyte chemoattractant protein-1 (MCP-1)
+** erythropoietin
+** vascular endothelial growth factor and vascular endothelial growth factor receptors
+** glucose transporters
+** glycolytic enzymes
+* Promotes inflammation through increased expression of cytokines and recruitment of macrophages
+* Leads to increased C-X-C chemokine receptor type 4 (CXCR-4) that leads to increased density of tumor associated macrophages
+* Promotes angiogenesis
+* Promotes pro-fibrotic pathway, resulting in altered extra-cellular matrix
+|-
+|style="background:#DCDCDC;" align="center" + |Vascular endothelial growth factor (VEGF)<ref name="pmid26573796">{{cite journal |vauthors=Liu Y, Metzinger MN, Lewellen KA, Cripps SN, Carey KD, Harper EI, Shi Z, Tarwater L, Grisoli A, Lee E, Slusarz A, Yang J, Loughran EA, Conley K, Johnson JJ, Klymenko Y, Bruney L, Liang Z, Dovichi NJ, Cheatham B, Leevy WM, Stack MS |title=Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages |journal=Cancer Res. |volume=75 |issue=23 |pages=5046–57 |date=December 2015 |pmid=26573796 |pmc=4668203 |doi=10.1158/0008-5472.CAN-15-0706 |url=}}</ref><ref name="pmid">{{cite journal |vauthors=Slaughter KN, Thai T, Penaroza S, Benbrook DM, Thavathiru E, Ding K, Nelson T, McMeekin DS, Moore KN |title=Measurements of adiposity as clinical biomarkers for first-line bevacizumab-based chemotherapy in epithelial ovarian cancer |journal=Gynecol. Oncol. |volume=133 |issue=1 |pages=11–5 |date=April 2014 |pmid= |doi=10.1016/j.ygyno.2014.01.031 |url=}}</ref>
+|
+* Increased levels observed in obesity
+|
+* Promotes angiogenesis
+* Promotes tumor cells growth
+* Promotes metastasis
+|-
+|style="background:#DCDCDC;" align="center" + |Insulin-like growth factor 1 (IGF-1)<ref name="pmid24935119">{{cite journal |vauthors=Park J, Morley TS, Kim M, Clegg DJ, Scherer PE |title=Obesity and cancer--mechanisms underlying tumour progression and recurrence |journal=Nat Rev Endocrinol |volume=10 |issue=8 |pages=455–465 |date=August 2014 |pmid=24935119 |pmc=4374431 |doi=10.1038/nrendo.2014.94 |url=}}</ref><ref name="pmid26338721">{{cite journal |vauthors=Vrachnis N, Iavazzo C, Iliodromiti Z, Sifakis S, Alexandrou A, Siristatidis C, Grigoriadis C, Botsis D, Creatsas G |title=Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives |journal=Arch. Gynecol. Obstet. |volume=293 |issue=2 |pages=239–46 |date=February 2016 |pmid=26338721 |doi=10.1007/s00404-015-3858-z |url=}}</ref><ref name="pmid17914107">{{cite journal |vauthors=Spentzos D, Cannistra SA, Grall F, Levine DA, Pillay K, Libermann TA, Mantzoros CS |title=IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer |journal=Endocr. Relat. Cancer |volume=14 |issue=3 |pages=781–90 |date=September 2007 |pmid=17914107 |doi=10.1677/ERC-06-0073 |url=}}</ref><ref name="pmid15229476">{{cite journal |vauthors=Pollak MN, Schernhammer ES, Hankinson SE |title=Insulin-like growth factors and neoplasia |journal=Nat. Rev. Cancer |volume=4 |issue=7 |pages=505–18 |date=July 2004 |pmid=15229476 |doi=10.1038/nrc1387 |url=}}</ref>
+|
+* Increased levels observed in obesity
+* Increased levels in diabetes mellitus patients
+|
+* Promotes tumor cells growth
+* Promotes angiogenesis
+* Inhibits apoptosis
+* Decreases sex hormone binding globulin, leading to increased levels of biologically available estrogen
+* Associated with increased levels of hypoxia inducible factor (HIF)
+* Correlates negatively with survival
+|-
+|style="background:#DCDCDC;" align="center" + |Estrogen<ref name="pmid24935119">{{cite journal |vauthors=Park J, Morley TS, Kim M, Clegg DJ, Scherer PE |title=Obesity and cancer--mechanisms underlying tumour progression and recurrence |journal=Nat Rev Endocrinol |volume=10 |issue=8 |pages=455–465 |date=August 2014 |pmid=24935119 |pmc=4374431 |doi=10.1038/nrendo.2014.94 |url=}}</ref><ref name="pmid24603706">{{cite journal |vauthors=Laws MJ, Kannan A, Pawar S, Haschek WM, Bagchi MK, Bagchi IC |title=Dysregulated estrogen receptor signaling in the hypothalamic-pituitary-ovarian axis leads to ovarian epithelial tumorigenesis in mice |journal=PLoS Genet. |volume=10 |issue=3 |pages=e1004230 |date=March 2014 |pmid=24603706 |pmc=3945209 |doi=10.1371/journal.pgen.1004230 |url=}}</ref><ref name="pmid26637268">{{cite journal |vauthors=Schairer C, Fuhrman BJ, Boyd-Morin J, Genkinger JM, Gail MH, Hoover RN, Ziegler RG |title=Quantifying the Role of Circulating Unconjugated Estradiol in Mediating the Body Mass Index-Breast Cancer Association |journal=Cancer Epidemiol. Biomarkers Prev. |volume=25 |issue=1 |pages=105–13 |date=January 2016 |pmid=26637268 |pmc=5555590 |doi=10.1158/1055-9965.EPI-15-0687 |url=}}</ref>
+|
+* Increased levels observed in obesity
+|
+* Promotes tumor cells growth through action as a mitogen
+* Associated with increased expression of insulin-like growth factor 1 (IGF-1) receptors
+|}
 ==References==
 {{reflist|2}}

Epithelial ovarian tumors pathophysiology: Difference between revisions

Latest revision as of 21:37, 8 October 2019

Overview

Pathophysiology

Embryogenesis

Structural Characteristics of Ovarian Surface Epithelium in Adults

Functions

Role of Hormones and Growth Factors on Surface Epithelium

The Origin of Neoplasia in Epithelial Ovarian Cancer: A Mystery to Solve

Ovarian Origin of Ovarian Epithelial Tumors

Secondary Müllerian System

The Origin of Epithelial Ovarian Tumors from Fallopian Tubes and Endometrium

The Origin of Mucinous Tumors of Gastrointestinal Type and Transitional Cell (Brenner) Tumors: Still a Mystery to Solve

Pathogenesis

Secondary Müllerian System

Hereditary Ovarian Carcinoma: An Understanding of Genome

The Role of BRCA1 Gene in DNA Repair

The Role of BRCA2 Gene in DNA Repair

The Connection Between BRCA1 and BRCA2

The Role of Mismatch Repair Genes

TP53 Mutations and Loss of Tumor Suppression

An Insight Into The Molecular Pathogenesis of Epithelial Ovarian Cancer

Dualistic Model

Dualistic Model for Serous Tumor

Genetic Alterations in Clear Cell

Genetic Alterations in Endometrioid Tumors

Genetic Alterations in Mucinous Tumors

Hereditary Epithelial Ovarian Carcinoma: An overview of Hereditary Syndromes and the Genetic Mutations

Hereditary Breast and Ovarian Cancer (HBOC)

Lynch Syndrome

Li-Fraumeni Syndrome

Site-Specific Ovarian Cancer

Cowden Syndrome

RAD51

PALB2

CHEK2

Mre11 Complex

BARD1

BRIP1

An attempt to explain the origin of carcinogenesis in sporadic epithelial carcinoma

Obesity: A Risk Factor for Epithelial Cancer

Diabetes Mellitus and The Risk of Epithelial Ovarian Cancer

Metabolic Syndrome and the Risk of Epithelial Ovarian Cancer

Pathogenesis of Epithelial Ovarian Cancer Associated with Metabolic Abnormalities

Cytokines and Adipokines

Immune Cells

Hormones, Signaling Pathways in Pathogenesis of Epithelial Ovarian Cancer and Their Link to Metabolic Risk Factors

References

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