Epithelial ovarian tumors pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
Line 128: Line 128:
* 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>
* 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.'''
'''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|A summary of BRCA1 activity and function in DNA damage repair]]


==== The role of BRCA2 gene in DNA repair ====
==== The role of BRCA2 gene in DNA repair ====

Revision as of 16:13, 22 February 2019


Epithelial ovarian tumors Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Epithelial Ovarian Tumors from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Epithelial ovarian tumors pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Epithelial ovarian tumors pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Epithelial ovarian tumors pathophysiology

CDC on Epithelial ovarian tumors pathophysiology

Epithelial ovarian tumors pathophysiology in the news

Blogs on Epithelial ovarian tumors pathophysiology

Directions to Hospitals Treating Psoriasis

Risk calculators and risk factors for Epithelial ovarian tumors pathophysiology

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

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[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 human 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

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.[23]
  • 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..[24][25]
  • 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.[26][25]
  • 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.[24][25]

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.[27][28]
  • 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.[27][28][29][30]

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.[27][28] [31]
  • 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.[31]
  • Tumor suppressor role of both domains is highlighted by the fact that mutations in both domains have been found in breast and gynecological malignancies.[31]
  • The major role of BRCA1 appears to sense and repair double stranded DNA breaks in homologous recombination.[31]

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.[31]
  • 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:[31]

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.

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).[27][28][31]
  • 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).[31][32]
  • 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.[31][32][33]
  • 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.[31][33]

The connection between BRCA1 and BRCA2

  • The common pathway that seems to link both BRCA! and BRCA2 proteins is homologous recombination mediated repair.[31][34][35]
  • Partner and localizer of BRCA2 (PALB2) physically connects BRCA1 and BRCA2 through N-terminal coiled-coil domain and the C terminus.[31][34][35]
  • 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.[31]

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.[27][28][29][30]
  • A simplified version of repair mechanism by mismatch repair genes products is described below:[30][36]

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.[29][30][36]

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.[37][38]
  • 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.[39][38]

Hereditary epithelial ovarian carcinoma: an overview of hereditary syndromes and the genes 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.[27][31]
  • 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.[27][31]
  • 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.[31][40][41]

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.[27][29][30]
  • A simplified version of repair mechanism by mismatch repair genes products is described below:[30][36]
  • 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).[27][42]
  • 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.[42]
  • Other malignancies that have been observed in lynch syndrome are gastric cancer, small bowel malignancies, hepatobiliary epithelial carcinoma, uroepithelial epithelial carcinoma and brain tumors.[42][43]

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.[37][38]
  • 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.[39][38]
  • 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.[39][44]
  • 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.[39][45]

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.[31][32][33][37]
  • 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.[37][46][47]

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.[31][34][35]
  • 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.[29][48][49]

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.[50][51]
  • 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.[29][52]

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).[29][53]
  • 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.[53][54]
  • Some studies have suggested an increased susceptibility to ovarian and breast cancers in hereditary mutations in Mre11 complex.[29][55]

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.[56][57]
  • Mutations in BARD1 have been associated with breast and ovarian cancer.[29][58]

BRIP1

  • BRCA1-interacting protein 1 (BRIP1) encodes for a helicase that interacts with BRCA1 in homologous recombination mediated repair of double stranded DNA breaks.[59][60]
  • 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.[60][61]

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

Proposed

hypothesis

Proposed

Mechanism

For Against
Incessant ovulation[1][62][63][64][65][66]
  • 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][66][67][68][69][70][71]
  • 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][65][66][72][73][74]
  • 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][70][75][76]
  • 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

An insight on molecular pathogenesis of epithelial ovarian cancer

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.[77][78]
  • Another advantage of this classification is that it tries to group precursor lesions with their putative malignant lesions.[77][78]
  • 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.[79][80]
  • Type II tumors generally arise from fallopian tubal epithelium. They exhibit more aggressive clinical course and a different genetic profile relative to Type I.[79][80]
  • 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.[77][78][81]
  • 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.[77][82][83]
  • 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.[77][78]
  • 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)”.[77][78][84]
  • 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.[77][85]
  • 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.[77][84]
  • 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:[77][86][87][88]

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.[77]

  • 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.[77][83]
  • 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.[77][89]
  • 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.[77][90]

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.[77][81][91]
  • Activating mutation of PIK3CA, also observed in about half of these tumors, results in actiavtion of PI3k pathway.[77][92]
  • Deletion of PTEN, observed in about 20% of the cases, results in loss of tumor suppressor gene.[77][93]
  • These alterations indicate the importance of PI3K/PTEN pathway in development of clear cell carcinoma of ovary.[77][93]

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.[77][94][95][96]
  • 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.[77][94][95][96]
  • 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.[77][96]

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.[77][97][98]

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.[24][25][77][99][100]
  • 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.[24][25][77][99][100][101]
  • 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.[77][99][100][102][103]

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.[77][99][100]
  • 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.[24][25][77][99][100][101]
  • 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.[77][99][100][102][103]
  • 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.[99][100]
  • 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.[77][99][100][104][102][105]
  • 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.[77][99][100][104][102][105]
  • 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.[77][99][100][106]
  • 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.[77][99][100]

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.[23][77][99][100]
  • 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.[24][77][99][100]
  • 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.[77][99][100][101]
  • Another apparent flaw is that transition of these cysts lined by Müllerian-type epithelium, although present, to carcinoma has been very rare.[77][99][100]

The origin of epithelial ovarian tumors from fallopian tubes and endometrium, and not from ovaries

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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.
  • 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.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Saad AF, Hu W, Sood AK (December 2010). "Microenvironment and pathogenesis of epithelial ovarian cancer". Horm Cancer. 1 (6): 277–90. doi:10.1007/s12672-010-0054-2. PMC 3199131. PMID 21761359.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC (April 2001). "Ovarian surface epithelium: biology, endocrinology, and pathology". Endocr. Rev. 22 (2): 255–88. doi:10.1210/edrv.22.2.0422. PMID 11294827.
  3. ↑ 3.0 3.1 Yoshinaga K, Hess DL, Hendrickx AG, Zamboni L (January 1988). "The development of the sexually indifferent gonad in the prosimian, Galago crassicaudatus crassicaudatus". Am. J. Anat. 181 (1): 89–105. doi:10.1002/aja.1001810110. PMID 3348150.
  4. ↑ 4.0 4.1 4.2 Siemens CH, Auersperg N (March 1988). "Serial propagation of human ovarian surface epithelium in tissue culture". J. Cell. Physiol. 134 (3): 347–56. doi:10.1002/jcp.1041340305. PMID 2450877.
  5. ↑ 5.0 5.1 5.2 Kruk PA, Uitto VJ, Firth JD, Dedhar S, Auersperg N (November 1994). "Reciprocal interactions between human ovarian surface epithelial cells and adjacent extracellular matrix". Exp. Cell Res. 215 (1): 97–108. doi:10.1006/excr.1994.1320. PMID 7525326.
  6. ↑ Davies BR, Worsley SD, Ponder BA (January 1998). "Expression of E-cadherin, alpha-catenin and beta-catenin in normal ovarian surface epithelium and epithelial ovarian cancers". Histopathology. 32 (1): 69–80. PMID 9522220.
  7. ↑ Sundfeldt K, Piontkewitz Y, Ivarsson K, Nilsson O, Hellberg P, Brännström M, Janson PO, Enerback S, Hedin L (June 1997). "E-cadherin expression in human epithelial ovarian cancer and normal ovary". Int. J. Cancer. 74 (3): 275–80. PMID 9221804.
  8. ↑ Osterholzer HO, Streibel EJ, Nicosia SV (August 1985). "Growth effects of protein hormones on cultured rabbit ovarian surface epithelial cells". Biol. Reprod. 33 (1): 247–58. PMID 3933584.
  9. ↑ Davies BR, Finnigan DS, Smith SK, Ponder BA (April 1999). "Administration of gonadotropins stimulates proliferation of normal mouse ovarian surface epithelium". Gynecol. Endocrinol. 13 (2): 75–81. PMID 10399050.
  10. ↑ Rodriguez GC, Berchuck A, Whitaker RS, Schlossman D, Clarke-Pearson DL, Bast RC (March 1991). "Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. II. Relationship between receptor expression and response to epidermal growth factor". Am. J. Obstet. Gynecol. 164 (3): 745–50. PMID 2003535.
  11. ↑ Evangelou A, Jindal SK, Brown TJ, Letarte M (February 2000). "Down-regulation of transforming growth factor beta receptors by androgen in ovarian cancer cells". Cancer Res. 60 (4): 929–35. PMID 10706107.
  12. ↑ Kang SK, Choi KC, Tai CJ, Auersperg N, Leung PC (February 2001). "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". Endocrinology. 142 (2): 580–8. doi:10.1210/endo.142.2.7982. PMID 11159828.
  13. ↑ Liu Y, Lin L, Zarnegar R (September 1994). "Modulation of hepatocyte growth factor gene expression by estrogen in mouse ovary". Mol. Cell. Endocrinol. 104 (2): 173–81. PMID 7988745.
  14. ↑ Basilico C, Moscatelli D (1992). "The FGF family of growth factors and oncogenes". Adv. Cancer Res. 59: 115–65. PMID 1381547.
  15. ↑ Dabrow MB, Francesco MR, McBrearty FX, Caradonna S (October 1998). "The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium". Gynecol. Oncol. 71 (1): 29–37. doi:10.1006/gyno.1998.5121. PMID 9784315.
  16. ↑ Wu S, Rodabaugh K, Martinez-Maza O, Watson JM, Silberstein DS, Boyer CM, Peters WP, Weinberg JB, Berek JS, Bast RC (March 1992). "Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-1, interleukin-6, and tumor necrosis factor-alpha". Am. J. Obstet. Gynecol. 166 (3): 997–1007. PMID 1550178.
  17. ↑ Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB, Bast RC (April 1993). "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". Cancer Res. 53 (8): 1939–44. PMID 8385577.
  18. ↑ Berchuck A, Rodriguez G, Olt G, Whitaker R, Boente MP, Arrick BA, Clarke-Pearson DL, Bast RC (February 1992). "Regulation of growth of normal ovarian epithelial cells and ovarian cancer cell lines by transforming growth factor-beta". Am. J. Obstet. Gynecol. 166 (2): 676–84. PMID 1536252.
  19. ↑ Parrott JA, Skinner MK (March 2000). "Expression and action of hepatocyte growth factor in human and bovine normal ovarian surface epithelium and ovarian cancer". Biol. Reprod. 62 (3): 491–500. PMID 10684788.
  20. ↑ Gulati R, Peluso JJ (May 1997). "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". Endocrinology. 138 (5): 1847–56. doi:10.1210/endo.138.5.5137. PMID 9112378.
  21. ↑ Ziltener HJ, Maines-Bandiera S, Schrader JW, Auersperg N (September 1993). "Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium". Biol. Reprod. 49 (3): 635–41. PMID 7691194.
  22. ↑ Marth C, Zeimet AG, Herold M, Brumm C, Windbichler G, Müller-Holzner E, Offner F, Feichtinger H, Zwierzina H, Daxenbichler G (September 1996). "Different effects of interferons, interleukin-1beta and tumor necrosis factor-alpha in normal (OSE) and malignant human ovarian epithelial cells". Int. J. Cancer. 67 (6): 826–30. doi:10.1002/(SICI)1097-0215(19960917)67:6<826::AID-IJC12>3.0.CO;2-#. PMID 8824555.
  23. ↑ 23.0 23.1 Devouassoux-Shisheboran M, Genestie C (January 2015). "Pathobiology of ovarian carcinomas". Chin J Cancer. 34 (1): 50–5. doi:10.5732/cjc.014.10273. PMC 4302089. PMID 25556618.
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 Devouassoux-Shisheboran M, Genestie C (January 2015). "Pathobiology of ovarian carcinomas". Chin J Cancer. 34 (1): 50–5. doi:10.5732/cjc.014.10273. PMC 4302089. PMID 25556618.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 Lauchlan SC (July 1984). "Metaplasias and neoplasias of Müllerian epithelium". Histopathology. 8 (4): 543–57. PMID 6090303.
  26. ↑ Devouassoux-Shisheboran M, Genestie C (January 2015). "Pathobiology of ovarian carcinomas". Chin J Cancer. 34 (1): 50–5. doi:10.5732/cjc.014.10273. PMC 4302089. PMID 25556618.
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 27.6 27.7 27.8 Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, Godwin AK (April 2009). "Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management". Mol Oncol. 3 (2): 97–137. doi:10.1016/j.molonc.2009.02.004. PMID 19383374.
  28. ↑ 28.0 28.1 28.2 28.3 28.4 Neff RT, Senter L, Salani R (August 2017). "BRCA mutation in ovarian cancer: testing, implications and treatment considerations". Ther Adv Med Oncol. 9 (8): 519–531. doi:10.1177/1758834017714993. PMID 28794804.
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 29.6 29.7 29.8 Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L (2015). "Hereditary ovarian cancer: not only BRCA 1 and 2 genes". Biomed Res Int. 2015: 341723. doi:10.1155/2015/341723. PMC 4449870. PMID 26075229.
  30. ↑ 30.0 30.1 30.2 30.3 30.4 30.5 Martín-López JV, Fishel R (June 2013). "The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome". Fam. Cancer. 12 (2): 159–68. doi:10.1007/s10689-013-9635-x. PMC 4235668. PMID 23572416.
  31. ↑ 31.00 31.01 31.02 31.03 31.04 31.05 31.06 31.07 31.08 31.09 31.10 31.11 31.12 31.13 31.14 31.15 31.16 31.17 Roy R, Chun J, Powell SN (December 2011). "BRCA1 and BRCA2: different roles in a common pathway of genome protection". Nat. Rev. Cancer. 12 (1): 68–78. doi:10.1038/nrc3181. PMC 4972490. PMID 22193408.
  32. ↑ 32.0 32.1 32.2 Thorslund T, McIlwraith MJ, Compton SA, Lekomtsev S, Petronczki M, Griffith JD, West SC (October 2010). "The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA". Nat. Struct. Mol. Biol. 17 (10): 1263–5. doi:10.1038/nsmb.1905. PMC 4041013. PMID 20729858.
  33. ↑ 33.0 33.1 33.2 Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK, Venkitaraman AR, Kowalczykowski SC (March 2009). "The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51". Cell. 136 (6): 1032–43. doi:10.1016/j.cell.2009.02.019. PMC 2669112. PMID 19303847.
  34. ↑ 34.0 34.1 34.2 Sy SM, Huen MS, Chen J (April 2009). "PALB2 is an integral component of the BRCA complex required for homologous recombination repair". Proc. Natl. Acad. Sci. U.S.A. 106 (17): 7155–60. doi:10.1073/pnas.0811159106. PMC 2678481. PMID 19369211.
  35. ↑ 35.0 35.1 35.2 Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM (June 2006). "Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2". Mol. Cell. 22 (6): 719–29. doi:10.1016/j.molcel.2006.05.022. PMID 16793542.
  36. ↑ 36.0 36.1 36.2 Hsieh P, Yamane K (2008). "DNA mismatch repair: molecular mechanism, cancer, and ageing". Mech. Ageing Dev. 129 (7–8): 391–407. doi:10.1016/j.mad.2008.02.012. PMC 2574955. PMID 18406444.
  37. ↑ 37.0 37.1 37.2 37.3 Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L (2015). "Hereditary ovarian cancer: not only BRCA 1 and 2 genes". Biomed Res Int. 2015: 341723. doi:10.1155/2015/341723. PMC 4449870. PMID 26075229.
  38. ↑ 38.0 38.1 38.2 38.3 Miller M, Shirole N, Tian R, Pal D, Sordella R (2016). "The Evolution of TP53 Mutations: From Loss-of-Function to Separation-of-Function Mutants". J Cancer Biol Res. 4 (4). PMC 5298884. PMID 28191499.
  39. ↑ 39.0 39.1 39.2 39.3 Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L (2015). "Hereditary ovarian cancer: not only BRCA 1 and 2 genes". Biomed Res Int. 2015: 341723. doi:10.1155/2015/341723. PMC 4449870. PMID 26075229.
  40. ↑ Fan S, Wang J, Yuan R, Ma Y, Meng Q, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID, Rosen EM (May 1999). "BRCA1 inhibition of estrogen receptor signaling in transfected cells". Science. 284 (5418): 1354–6. PMID 10334989.
  41. ↑ Hamada J, Nakata D, Nakae D, Kobayashi Y, Akai H, Konishi Y, Okada F, Shibata T, Hosokawa M, Moriuchi T (February 2001). "Increased oxidative DNA damage in mammary tumor cells by continuous epidermal growth factor stimulation". J. Natl. Cancer Inst. 93 (3): 214–9. PMID 11158190.
  42. ↑ 42.0 42.1 42.2 Sehgal R, Sheahan K, O'Connell PR, Hanly AM, Martin ST, Winter DC (June 2014). "Lynch syndrome: an updated review". Genes (Basel). 5 (3): 497–507. doi:10.3390/genes5030497. PMC 4198913. PMID 24978665.
  43. ↑ 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 (December 2008). "Feasibility of screening for Lynch syndrome among patients with colorectal cancer". J. Clin. Oncol. 26 (35): 5783–8. doi:10.1200/JCO.2008.17.5950. PMC 2645108. PMID 18809606.
  44. ↑ Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, Bouffet E, Malkin D, Hawkins C (March 2010). "Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations". J. Clin. Oncol. 28 (8): 1345–50. doi:10.1200/JCO.2009.23.5952. PMID 20142599.
  45. ↑ Levine AJ, Momand J, Finlay CA (June 1991). "The p53 tumour suppressor gene". Nature. 351 (6326): 453–6. doi:10.1038/351453a0. PMID 2046748.
  46. ↑ 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 (August 2011). "Germline mutations in RAD51D confer susceptibility to ovarian cancer". Nat. Genet. 43 (9): 879–882. doi:10.1038/ng.893. PMC 4845885. PMID 21822267.
  47. ↑ 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 (May 2010). "Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene". Nat. Genet. 42 (5): 410–4. doi:10.1038/ng.569. PMID 20400964.
  48. ↑ Casadei S, Norquist BM, Walsh T, Stray S, Mandell JB, Lee MK, Stamatoyannopoulos JA, King MC (March 2011). "Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer". Cancer Res. 71 (6): 2222–9. doi:10.1158/0008-5472.CAN-10-3958. PMC 3059378. PMID 21285249.
  49. ↑ Poumpouridou N, Kroupis C (December 2011). "Hereditary breast cancer: beyond BRCA genetic analysis; PALB2 emerges". Clin. Chem. Lab. Med. 50 (3): 423–34. doi:10.1515/cclm-2011-0840. PMID 22505525.
  50. ↑ "CHEK2 gene - Genetics Home Reference - NIH".
  51. ↑ Cai Z, Chehab NH, Pavletich NP (September 2009). "Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase". Mol. Cell. 35 (6): 818–29. doi:10.1016/j.molcel.2009.09.007. PMID 19782031.
  52. ↑ 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 (May 2002). "Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations". Nat. Genet. 31 (1): 55–9. doi:10.1038/ng879. PMID 11967536.
  53. ↑ 53.0 53.1 Stracker TH, Petrini JH (February 2011). "The MRE11 complex: starting from the ends". Nat. Rev. Mol. Cell Biol. 12 (2): 90–103. doi:10.1038/nrm3047. PMC 3905242. PMID 21252998.
  54. ↑ Lamarche BJ, Orazio NI, Weitzman MD (September 2010). "The MRN complex in double-strand break repair and telomere maintenance". FEBS Lett. 584 (17): 3682–95. doi:10.1016/j.febslet.2010.07.029. PMC 2946096. PMID 20655309.
  55. ↑ Heikkinen K, Karppinen SM, Soini Y, Mäkinen M, Winqvist R (December 2003). "Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility". J. Med. Genet. 40 (12): e131. PMC 1735331. PMID 14684699.
  56. ↑ Westermark UK, Reyngold M, Olshen AB, Baer R, Jasin M, Moynahan ME (November 2003). "BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks". Mol. Cell. Biol. 23 (21): 7926–36. PMID 14560035.
  57. ↑ Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE (October 2001). "Structure of a BRCA1-BARD1 heterodimeric RING-RING complex". Nat. Struct. Biol. 8 (10): 833–7. doi:10.1038/nsb1001-833. PMID 11573085.
  58. ↑ 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 (May 2015). "Analysis of large mutations in BARD1 in patients with breast and/or ovarian cancer: the Polish population as an example". Sci Rep. 5: 10424. doi:10.1038/srep10424. PMID 25994375.
  59. ↑ [++++https://ghr.nlm.nih.gov/gene/BRIP1 "BRIP1 gene - Genetics Home Reference - NIH"] Check |url= value (help).
  60. ↑ 60.0 60.1 Ring KL, Garcia C, Thomas MH, Modesitt SC (November 2017). "Current and future role of genetic screening in gynecologic malignancies". Am. J. Obstet. Gynecol. 217 (5): 512–521. doi:10.1016/j.ajog.2017.04.011. PMID 28411145.
  61. ↑ 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 (January 2018). "BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer". Breast Cancer Res. 20 (1): 7. doi:10.1186/s13058-018-0935-9. PMC 5784717. PMID 29368626.
  62. ↑ Riman T, Dickman PW, Nilsson S, Correia N, Nordlinder H, Magnusson CM, Persson IR (August 2002). "Risk factors for invasive epithelial ovarian cancer: results from a Swedish case-control study". Am. J. Epidemiol. 156 (4): 363–73. PMID 12181107.
  63. ↑ Gwinn ML, Lee NC, Rhodes PH, Layde PM, Rubin GL (1990). "Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer". J Clin Epidemiol. 43 (6): 559–68. PMID 2348208.
  64. ↑ Nasca PC, Greenwald P, Chorost S, Richart R, Caputo T (May 1984). "An epidemiologic case-control study of ovarian cancer and reproductive factors". Am. J. Epidemiol. 119 (5): 705–13. PMID 6539067.
  65. ↑ 65.0 65.1 Risch HA (December 1998). "Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone". J. Natl. Cancer Inst. 90 (23): 1774–86. PMID 9839517.
  66. ↑ 66.0 66.1 66.2 Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C (October 1996). "Epithelial ovarian cancer risk among women with polycystic ovary syndrome". Obstet Gynecol. 88 (4 Pt 1): 554–9. PMID 8841217.
  67. ↑ Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC (May 2002). "Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovarian surface epithelial cells". J. Clin. Endocrinol. Metab. 87 (5): 2245–53. doi:10.1210/jcem.87.5.8506. PMID 11994371.
  68. ↑ Lau MT, Wong AS, Leung PC (July 2010). "Gonadotropins induce tumor cell migration and invasion by increasing cyclooxygenases expression and prostaglandin E(2) production in human ovarian cancer cells". Endocrinology. 151 (7): 2985–93. doi:10.1210/en.2009-1318. PMID 20392831.
  69. ↑ Choi JH, Choi KC, Auersperg N, Leung PC (November 2004). "Overexpression of follicle-stimulating hormone receptor activates oncogenic pathways in preneoplastic ovarian surface epithelial cells". J. Clin. Endocrinol. Metab. 89 (11): 5508–16. doi:10.1210/jc.2004-0044. PMID 15531506.
  70. ↑ 70.0 70.1 Ness RB, Cottreau C (September 1999). "Possible role of ovarian epithelial inflammation in ovarian cancer". J. Natl. Cancer Inst. 91 (17): 1459–67. PMID 10469746.
  71. ↑ Zheng W, Lu JJ, Luo F, Zheng Y, Feng Y, Felix JC, Lauchlan SC, Pike MC (January 2000). "Ovarian epithelial tumor growth promotion by follicle-stimulating hormone and inhibition of the effect by luteinizing hormone". Gynecol. Oncol. 76 (1): 80–8. doi:10.1006/gyno.1999.5628. PMID 10620446. Vancouver style error: initials (help)
  72. ↑ Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Lewis JL, Strom BL, Harlap S, Shapiro S (April 1994). "A case-control study of oral contraceptive use and invasive epithelial ovarian cancer". Am. J. Epidemiol. 139 (7): 654–61. PMID 8166126.
  73. ↑ Edmondson RJ, Monaghan JM, Davies BR (March 2002). "The human ovarian surface epithelium is an androgen responsive tissue". Br. J. Cancer. 86 (6): 879–85. doi:10.1038/sj.bjc.6600154. PMC 2364138. PMID 11953818.
  74. ↑ Seeger H, Wallwiener D, Mueck AO (2006). "Is there a protective role of progestogens on the proliferation of human ovarian cancer cells in the presence of growth factors?". Eur. J. Gynaecol. Oncol. 27 (2): 139–41. PMID 16620055.
  75. ↑ Altinoz MA, Korkmaz R (2004). "NF-kappaB, macrophage migration inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the acetaminophen- and NSAID-prevention of the ovarian cancer". Neoplasma. 51 (4): 239–47. PMID 15254653.
  76. ↑ Heller DS, Westhoff C, Gordon RE, Katz N (May 1996). "The relationship between perineal cosmetic talc usage and ovarian talc particle burden". Am. J. Obstet. Gynecol. 174 (5): 1507–10. PMID 9065120.
  77. ↑ 77.00 77.01 77.02 77.03 77.04 77.05 77.06 77.07 77.08 77.09 77.10 77.11 77.12 77.13 77.14 77.15 77.16 77.17 77.18 77.19 77.20 77.21 77.22 77.23 77.24 77.25 77.26 77.27 77.28 77.29 77.30 77.31 77.32 77.33 77.34 Kurman RJ, Shih I (July 2011). "Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm". Hum. Pathol. 42 (7): 918–31. doi:10.1016/j.humpath.2011.03.003. PMID 21683865. Vancouver style error: initials (help)
  78. ↑ 78.0 78.1 78.2 78.3 78.4 Shih I, Kurman RJ (May 2004). "Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis". Am. J. Pathol. 164 (5): 1511–8. PMID 15111296. Vancouver style error: initials (help)
  79. ↑ 79.0 79.1 Rojas V, Hirshfield KM, Ganesan S, Rodriguez-Rodriguez L (December 2016). "Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment". Int J Mol Sci. 17 (12). doi:10.3390/ijms17122113. PMC 5187913. PMID 27983698.
  80. ↑ 80.0 80.1 McCluggage WG (August 2011). "Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis". Pathology. 43 (5): 420–32. doi:10.1097/PAT.0b013e328348a6e7. PMID 21716157.
  81. ↑ 81.0 81.1 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 I, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG (October 2010). "ARID1A mutations in endometriosis-associated ovarian carcinomas". N. Engl. J. Med. 363 (16): 1532–43. doi:10.1056/NEJMoa1008433. PMC 2976679. PMID 20942669. Vancouver style error: initials (help)
  82. ↑ Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, Stewart C, Fereday S, Caldas C, Defazio A, Bowtell D, Brenton JD (May 2010). "Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary". J. Pathol. 221 (1): 49–56. doi:10.1002/path.2696. PMC 3262968. PMID 20229506.
  83. ↑ 83.0 83.1 Senturk E, Cohen S, Dottino PR, Martignetti JA (November 2010). "A critical re-appraisal of BRCA1 methylation studies in ovarian cancer". Gynecol. Oncol. 119 (2): 376–83. doi:10.1016/j.ygyno.2010.07.026. PMID 20797776.
  84. ↑ 84.0 84.1 Burks RT, Sherman ME, Kurman RJ (November 1996). "Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors". Am. J. Surg. Pathol. 20 (11): 1319–30. PMID 8898836.
  85. ↑ Ho CL, Kurman RJ, Dehari R, Wang TL, Shih I (October 2004). "Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors". Cancer Res. 64 (19): 6915–8. doi:10.1158/0008-5472.CAN-04-2067. PMID 15466181. Vancouver style error: initials (help)
  86. ↑ Singer G, Oldt R, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih I (March 2003). "Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma". J. Natl. Cancer Inst. 95 (6): 484–6. PMID 12644542. Vancouver style error: initials (help)
  87. ↑ Mayr D, Hirschmann A, Löhrs U, Diebold J (December 2006). "KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants". Gynecol. Oncol. 103 (3): 883–7. doi:10.1016/j.ygyno.2006.05.029. PMID 16806438.
  88. ↑ Hsu CY, Bristow R, Cha MS, Wang BG, Ho CL, Kurman RJ, Wang TL, Shih I (October 2004). "Characterization of active mitogen-activated protein kinase in ovarian serous carcinomas". Clin. Cancer Res. 10 (19): 6432–6. doi:10.1158/1078-0432.CCR-04-0893. PMID 15475429. Vancouver style error: initials (help)
  89. ↑ May T, Virtanen C, Sharma M, Milea A, Begley H, Rosen B, Murphy KJ, Brown TJ, Shaw PA (April 2010). "Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary". Gynecol. Oncol. 117 (1): 9–17. doi:10.1016/j.ygyno.2010.01.006. PMID 20117829.
  90. ↑ Nakayama K, Nakayama N, Jinawath N, Salani R, Kurman RJ, Shih I, Wang TL (June 2007). "Amplicon profiles in ovarian serous carcinomas". Int. J. Cancer. 120 (12): 2613–7. doi:10.1002/ijc.22609. PMID 17351921. Vancouver style error: initials (help)
  91. ↑ Jones S, Wang TL, Shih I, Mao TL, Nakayama K, Roden R, Glas R, Slamon D, Diaz LA, Vogelstein B, Kinzler KW, Velculescu VE, Papadopoulos N (October 2010). "Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma". Science. 330 (6001): 228–31. doi:10.1126/science.1196333. PMC 3076894. PMID 20826764. Vancouver style error: initials (help)
  92. ↑ Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA (November 2004). "Mutation of the PIK3CA gene in ovarian and breast cancer". Cancer Res. 64 (21): 7678–81. doi:10.1158/0008-5472.CAN-04-2933. PMID 15520168.
  93. ↑ 93.0 93.1 Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y, Kubo T, Noguchi M (December 2000). "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". Cancer Res. 60 (24): 7052–6. PMID 11156411.
  94. ↑ 94.0 94.1 Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix-Trench G, Thomas EJ, Campbell IG (May 1998). "Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors". Cancer Res. 58 (10): 2095–7. PMID 9605750.
  95. ↑ 95.0 95.1 Catasús L, Bussaglia E, Rodrguez I, Gallardo A, Pons C, Irving JA, Prat J (November 2004). "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". Hum. Pathol. 35 (11): 1360–8. doi:10.1016/j.humpath.2004.07.019. PMID 15668893.
  96. ↑ 96.0 96.1 96.2 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 (April 2007). "Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways". Cancer Cell. 11 (4): 321–33. doi:10.1016/j.ccr.2007.02.016. PMID 17418409.
  97. ↑ Ichikawa Y, Nishida M, Suzuki H, Yoshida S, Tsunoda H, Kubo T, Uchida K, Miwa M (January 1994). "Mutation of K-ras protooncogene is associated with histological subtypes in human mucinous ovarian tumors". Cancer Res. 54 (1): 33–5. PMID 8261457.
  98. ↑ Gemignani ML, Schlaerth AC, Bogomolniy F, Barakat RR, Lin O, Soslow R, Venkatraman E, Boyd J (August 2003). "Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma". Gynecol. Oncol. 90 (2): 378–81. PMID 12893203.
  99. ↑ 99.00 99.01 99.02 99.03 99.04 99.05 99.06 99.07 99.08 99.09 99.10 99.11 99.12 99.13 99.14 Dubeau L (December 2008). "The cell of origin of ovarian epithelial tumours". Lancet Oncol. 9 (12): 1191–7. doi:10.1016/S1470-2045(08)70308-5. PMC 4176875. PMID 19038766.
  100. ↑ 100.00 100.01 100.02 100.03 100.04 100.05 100.06 100.07 100.08 100.09 100.10 100.11 100.12 100.13 100.14 Kurman RJ, Shih I (April 2008). "Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications". Int. J. Gynecol. Pathol. 27 (2): 151–60. doi:10.1097/PGP.0b013e318161e4f5. PMC 2794425. PMID 18317228. Vancouver style error: initials (help)
  101. ↑ 101.0 101.1 101.2 Riopel MA, Ronnett BM, Kurman RJ (June 1999). "Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas". Am. J. Surg. Pathol. 23 (6): 617–35. PMID 10366144.
  102. ↑ 102.0 102.1 102.2 102.3 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 (February 2007). "Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship". Am. J. Surg. Pathol. 31 (2): 161–9. doi:10.1097/01.pas.0000213335.40358.47. PMID 17255760.
  103. ↑ 103.0 103.1 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 (September 2005). "Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon". Clin. Cancer Res. 11 (17): 6116–26. doi:10.1158/1078-0432.CCR-04-2509. PMID 16144910.
  104. ↑ 104.0 104.1 Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, Feltmate CM, Berkowitz RS, Muto MG (September 2007). "Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction". J. Clin. Oncol. 25 (25): 3985–90. doi:10.1200/JCO.2007.12.2622. PMID 17761984.
  105. ↑ 105.0 105.1 Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, Verheijen RH (November 2001). "Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer". J. Pathol. 195 (4): 451–6. doi:10.1002/path.1000. PMID 11745677.
  106. ↑ 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 (April 2010). "Genetic analysis of the early natural history of epithelial ovarian carcinoma". PLoS ONE. 5 (4): e10358. doi:10.1371/journal.pone.0010358. PMC 2859950. PMID 20436685.
Retrieved from "https://www.wikidoc.org/index.php?title=Epithelial_ovarian_tumors_pathophysiology&oldid=1553531"