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| ==Overview== | | ==Overview== |
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| == Pathogenesis ==
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| [[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>]]
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| === Secondary Müllerian system ===
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| * 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>
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| * 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>
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| * 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>
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| * 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>
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| === Hereditary ovarian carcinoma: An understanding of genome ===
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| * 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>
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| * 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>
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| ==== The role of BRCA1 gene in DNA repair ====
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| * 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>
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| * 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>
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| * 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>
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| * 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>
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| '''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'''
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| * 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>
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| * 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>
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| '''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.'''
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| [[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>''']]
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| ==== The role of BRCA2 gene in DNA repair ====
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| * 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>
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| * 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>
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| * 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>
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| * 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>
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| ==== The connection between BRCA1 and BRCA2 ====
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| * 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>
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| * 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>
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| * 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>
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| ==== The role of mismatch repair genes ====
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| * 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>
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| * 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>
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| '''MutS homologs (MSHs) recognize the DNA mismatch → MutS homologs (MSHs) recruit MutL homologs (''MLHs)'' → excision of mismatched DNA → DNA polymerase re-synthesizes DNA.'''
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| * 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>
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| [[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]]]
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| ==== TP53 mutations and loss of tumor suppression ====
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| * 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>
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| * 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>
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| [[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>]]
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| {{Epithelial ovarian cancer}}
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| === An insight on molecular pathogenesis of epithelial ovarian cancer ===
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| [[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]]
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| ==== Dualistic Model ====
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| * 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>
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| * '''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
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| * 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]]
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|
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| ==== Genetic alterations in endometrioid tumors ====
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| * 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>
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| * 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>
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| * 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>
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| ==== Genetic alterations in mucinous tumors ====
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| * 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>
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| ==References== | | ==References== |
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