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Genetic epidemiology of ovarian cancer and prospects for polygenic risk prediction

  • Michelle R. Jones
    Affiliations
    Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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  • Daniella Kamara
    Affiliations
    Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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  • Beth Y. Karlan
    Affiliations
    Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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  • Paul D.P. Pharoah
    Affiliations
    CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
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  • Simon A. Gayther
    Correspondence
    Corresponding author at: Department of Biomedical Sciences, Cedars Sinai Medical Center, Samuel Oschin Cancer Institute, Steven Spielberg Building, 8725 Alden Dr. Room SSB 159, Los Angeles, CA 90048, USA.
    Affiliations
    Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Published:October 17, 2017DOI:https://doi.org/10.1016/j.ygyno.2017.10.001

      Highlights

      • Contribution of high and moderate penetrant genes to ovarian cancer heritability
      • Contribution of common low risk alleles to ovarian cancer heritability
      • Implications of genetic risk discovery for clinical risk prediction and prevention

      Abstract

      Epithelial ovarian cancer (EOC) is a heterogeneous disease with a major heritable component. The different histotypes of invasive disease – high grade serous, clear cell, endometrioid and mucinous – are associated with different underlying genetic susceptibility and epidemiological and lifestyle risk factors, all of which contribute to the different biology and clinical characteristics of each histotype. A combination of familial and population based sequencing studies, and genome wide association studies (GWAS) have identified a range of genetic susceptibility alleles for EOC comprising rare but highly penetrant genes (e.g. BRCA1, BRCA2) that are responsible for familial clustering of ovarian cancer cases; more moderate penetrance susceptibility genes (e.g. BRIP1, RAD51C/D, MSH6); and multiple common but low penetrance susceptibility alleles identified by GWAS. Identifying genetic risk alleles for ovarian cancer has had a significant impact on disease prevention strategies; for example it is now routine clinical practice for individuals with germline BRCA1 and BRCA2 mutations to undergo risk reducing salpingo-oophorectomy. Because ovarian cancers are commonly diagnosed at a late clinical stage when the prognosis is poor, the continued development of genetic risk prediction and prevention strategies will represent an important approach to reduce mortality due to ovarian cancer. Advances in genomics technologies that enable more high-throughput genetic testing, combined with research studies that identify additional EOC risk alleles will likely provide further opportunities to establish polygenic risk prediction approaches, based on combinations of rare high/moderate penetrance susceptibility genes and common, low penetrance susceptibility alleles. This article reviews the current literature describing the genetic and epidemiological components of ovarian cancer risk, and discusses both the opportunities and challenges in using this information for clinical risk prediction and prevention.

      Keywords

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      References

        • Patch A.M.
        • Christie E.L.
        • Etemadmoghadam D.
        • Garsed D.W.
        • George J.
        • Fereday S.
        • et al.
        Whole-genome characterization of chemoresistant ovarian cancer.
        Nature. 2015; 521: 489-494
        • The Cancer Genome Atlas
        Integrated genomic analyses of ovarian carcinoma.
        Nature. 2011; 474: 609-615
        • Seiden M.V.
        Gynecologic malignancies.
        in: Longo D.L. Harrison T.R. Harrison's Principles of Internal Medicine. 18th ed. McGraw-Hill, New York2012
        • Tcherkassova J.
        • Abramovich C.
        • Moro R.
        • Chen C.
        • Schmit R.
        • Gerber A.
        • et al.
        Combination of CA125 and RECAF biomarkers for early detection of ovarian cancer.
        Tumour Biol. 2011; 32: 831-838
        • Anton C.
        • Carvalho F.M.
        • Oliveira E.I.
        • Maciel G.A.
        • Baracat E.C.
        • Carvalho J.P.
        A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses.
        Clinics (Sao Paulo). 2012; 67: 437-441
        • Karlan B.Y.
        • Thorpe J.
        • Watabayashi K.
        • Drescher C.W.
        • Palomares M.
        • Daly M.B.
        • et al.
        Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women.
        Cancer Epidemiol. Biomarkers Prev. 2014; 23: 1383-1393
        • Guerriero S.
        • Alcazar J.L.
        • Ajossa S.
        • Galvan R.
        • Laparte C.
        • Garcia-Manero M.
        • et al.
        Transvaginal color Doppler imaging in the detection of ovarian cancer in a large study population.
        Int. J. Gynecol. Cancer. 2010; 20: 781-786
        • Risch H.A.
        Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone.
        J. Natl. Cancer Inst. 1998; 90: 1774-1786
        • Beral V.
        • Doll R.
        • Hermon C.
        • Peto R.
        • Reeves G.
        • Collaborative Group on Epidemiological Studies of Ovarian C
        Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls.
        Lancet. 2008; 371: 303-314
        • Adami H.O.
        • Hsieh C.C.
        • Lambe M.
        • Trichopoulos D.
        • Leon D.
        • Persson I.
        • et al.
        Parity, age at first childbirth, and risk of ovarian cancer.
        Lancet. 1994; 344: 1250-1254
        • Coughlin S.S.
        • Giustozzi A.
        • Smith S.J.
        • Lee N.C.A.
        meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer.
        J. Clin. Epidemiol. 2000; 53: 367-375
        • Pearce C.L.
        • Chung K.
        • Pike M.C.
        • Wu A.H.
        Increased ovarian cancer risk associated with menopausal estrogen therapy is reduced by adding a progestin.
        Cancer. 2009; 115: 531-539
        • Rossing M.A.
        • Cushing-Haugen K.L.
        • Wicklund K.G.
        • Doherty J.A.
        • Weiss N.S.
        Menopausal hormone therapy and risk of epithelial ovarian cancer.
        Cancer Epidemiol. Biomarkers Prev. 2007; 16: 2548-2556
        • Zhou B.
        • Sun Q.
        • Cong R.
        • Gu H.
        • Tang N.
        • Yang L.
        • et al.
        Hormone replacement therapy and ovarian cancer risk: a meta-analysis.
        Gynecol Oncol. 2008; 108: 641-651
        • Yang H.P.
        • Trabert B.
        • Murphy M.A.
        • Sherman M.E.
        • Sampson J.N.
        • Brinton L.A.
        • et al.
        Ovarian cancer risk factors by histologic subtypes in the NIH-AARP Diet and Health Study.
        Int. J. Cancer. 2012; 131: 938-948
        • Trabert B.
        • Wentzensen N.
        • Yang H.P.
        • Sherman M.E.
        • Hollenbeck A.
        • Danforth K.N.
        • et al.
        Ovarian cancer and menopausal hormone therapy in the NIH-AARP diet and health study.
        Br. J. Cancer. 2012; 107: 1181-1187
        • McSorley M.A.
        • Alberg A.J.
        • Allen D.S.
        • Allen N.E.
        • Brinton L.A.
        • Dorgan J.F.
        • et al.
        Prediagnostic circulating follicle stimulating hormone concentrations and ovarian cancer risk.
        Int. J. Cancer. 2009; 125: 674-679
        • Beral V.
        • Bull D.
        • Green J.
        • Reeves G.
        Ovarian cancer and hormone replacement therapy in the Million Women Study.
        Lancet. 2007; 369: 1703-1710
      1. Lacey JV, Jr., Mink PJ, Lubin JH, Sherman ME, Troisi R, Hartge P, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334-41.

      2. Lacey JV, Jr., Brinton LA, Leitzmann MF, Mouw T, Hollenbeck A, Schatzkin A, et al. Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health-AARP Diet and Health Study Cohort. J. Natl. Cancer Inst. 2006;98:1397-405.

        • Tsilidis K.K.
        • Allen N.E.
        • Key T.J.
        • Dossus L.
        • Kaaks R.
        • Bakken K.
        • et al.
        Menopausal hormone therapy and risk of ovarian cancer in the European prospective investigation into cancer and nutrition.
        Cancer Causes Control. 2011; 22: 1075-1084
        • Sieh W.
        • Salvador S.
        • McGuire V.
        • Weber R.P.
        • Terry K.L.
        • Rossing M.A.
        • et al.
        Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies.
        Int. J. Epidemiol. 2013; 42: 579-589
        • Olsen C.M.
        • Nagle C.M.
        • Whiteman D.C.
        • Ness R.
        • Pearce C.L.
        • Pike M.C.
        • et al.
        Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium.
        Endocr. Relat. Cancer. 2013; 20: 251-262
        • Pearce C.L.
        • Templeman C.
        • Rossing M.A.
        • Lee A.
        • Near A.M.
        • Webb P.M.
        • et al.
        Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies.
        Lancet Oncol. 2012; 13: 385-394
        • Beral V.
        • Gaitskell K.
        • Hermon C.
        • Moser K.
        • Reeves G.
        • Peto R.
        Ovarian cancer and smoking: individual participant meta-analysis including 28,114 women with ovarian cancer from 51 epidemiological studies.
        Lancet Oncol. 2012; 13: 946-956
        • Cook L.S.
        • Pestak C.R.
        • Leung A.C.
        • Steed H.
        • Nation J.
        • Swenerton K.
        • et al.
        Combined oral contraceptive use before the first birth and epithelial ovarian cancer risk.
        Br. J. Cancer. 2017; 116: 265-269
        • Wentzensen N.
        • Poole E.M.
        • Trabert B.
        • White E.
        • Arslan A.A.
        • Patel A.V.
        • et al.
        Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium.
        J. Clin. Oncol. 2016; 34: 2888-2898
        • Lichtenstein P.
        • Holm N.V.
        • Verkasalo P.K.
        • Iliadou A.
        • Kaprio J.
        • Koskenvuo M.
        • et al.
        Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland.
        N. Engl. J. Med. 2000; 343: 78-85
        • Miki Y.
        • Swensen J.
        • Shattuck-Eidens D.
        • Futreal P.A.
        • Harshman K.
        • Tavtigian S.
        • et al.
        A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
        Science. 1994; 266: 66-71
        • Wooster R.
        • Bignell G.
        • Lancaster J.
        • Swift S.
        • Seal S.
        • Mangion J.
        • et al.
        Identification of the breast cancer susceptibility gene BRCA2.
        Nature. 1995; 378: 789-792
        • Miki Y.
        • Swensen J.
        • Shattuck-Eidens D.
        • Futreal P.A.
        • Harshman K.
        • Tavtigian S.
        • et al.
        A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
        Science. 1994; 266: 66-71
        • Kuchenbaecker K.B.
        • Hopper J.L.
        • Barnes D.R.
        • Phillips K.A.
        • Mooij T.M.
        • Roos-Blom M.J.
        • et al.
        Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
        JAMA. 2017; 317: 2402-2416
        • Antoniou A.
        • Pharoah P.D.
        • Narod S.
        • Risch H.A.
        • Eyfjord J.E.
        • Hopper J.L.
        • et al.
        Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies.
        Am. J. Hum. Genet. 2003; 72: 1117-1130
        • King M.C.
        • Marks J.H.
        • Mandell J.B.
        New York Breast Cancer Study G. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.
        Science. 2003; 302: 643-646
        • Ford D.
        • Easton D.F.
        • Stratton M.
        • Narod S.
        • Goldgar D.
        • Devilee P.
        • et al.
        Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.
        Am. J. Hum. Genet. 1998; 62: 676-689
        • Gayther S.A.
        • Russell P.
        • Harrington P.
        • Antoniou A.C.
        • Easton D.F.
        • Ponder B.A.
        The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes.
        Am. J. Hum. Genet. 1999; 65: 1021-1029
        • Alsop K.
        • Fereday S.
        • Meldrum C.
        • deFazio A.
        • Emmanuel C.
        • George J.
        • et al.
        BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group.
        J. Clin. Oncol. 2012; 30: 2654-2663
        • Gayther S.A.
        • Warren W.
        • Mazoyer S.
        • Russell P.A.
        • Harrington P.A.
        • Chiano M.
        • et al.
        Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.
        Nat. Genet. 1995; 11: 428-433
        • Gayther S.A.
        • Mangion J.
        • Russell P.
        • Seal S.
        • Barfoot R.
        • Ponder B.A.
        • et al.
        Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.
        Nat. Genet. 1997; 15: 103-105
        • Thompson D.
        • Easton D.
        Variation in BRCA1 cancer risks by mutation position.
        Cancer Epidemiol. Biomarkers Prev. 2002; 11: 329-336
        • Thompson D.
        • Easton D.
        Breast cancer linkage C. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers.
        Am. J. Hum. Genet. 2001; 68: 410-419
        • Rebbeck T.R.
        • Mitra N.
        • Wan F.
        • Sinilnikova O.M.
        • Healey S.
        • McGuffog L.
        • et al.
        Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
        JAMA. 2015; 313: 1347-1361
        • Dine J.
        • Deng C.X.
        Mouse models of BRCA1 and their application to breast cancer research.
        Cancer Metastasis Rev. 2013; 32: 25-37
        • Evers B.
        • Jonkers J.
        Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects.
        Oncogene. 2006; 25: 5885-5897
        • Couch F.J.
        • Wang X.
        • McGuffog L.
        • Lee A.
        • Olswold C.
        • Kuchenbaecker K.B.
        • et al.
        Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.
        PLoS Genet. 2013; 9e1003212
        • Kuchenbaecker K.B.
        • Ramus S.J.
        • Tyrer J.
        • Lee A.
        • Shen H.C.
        • Beesley J.
        • et al.
        Identification of six new susceptibility loci for invasive epithelial ovarian cancer.
        Nat. Genet. 2015; 47: 164-171
        • Song H.
        • Cicek M.S.
        • Dicks E.
        • Harrington P.
        • Ramus S.J.
        • Cunningham J.M.
        • et al.
        The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population.
        Hum. Mol. Genet. 2014; 23: 4703-4709
        • Ramus S.J.
        • Harrington P.A.
        • Pye C.
        • DiCioccio R.A.
        • Cox M.J.
        • Garlinghouse-Jones K.
        • et al.
        Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer.
        Hum. Mutat. 2007; 28: 1207-1215
        • Soegaard M.
        • Kjaer S.K.
        • Cox M.
        • Wozniak E.
        • Hogdall E.
        • Hogdall C.
        • et al.
        BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark.
        Clin. Cancer Res. 2008; 14: 3761-3767
        • Yoshida K.
        • Miki Y.
        Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage.
        Cancer Sci. 2004; 95: 866-871
        • Hoeijmakers J.H.
        Genome maintenance mechanisms for preventing cancer.
        Nature. 2001; 411: 366-374
        • Meindl A.
        • Hellebrand H.
        • Wiek C.
        • Erven V.
        • Wappenschmidt B.
        • Niederacher D.
        • et al.
        Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.
        Nat. Genet. 2010; 42: 410-414
        • Loveday C.
        • Turnbull C.
        • Ramsay E.
        • Hughes D.
        • Ruark E.
        • Frankum J.R.
        • et al.
        Germline mutations in RAD51D confer susceptibility to ovarian cancer.
        Nat. Genet. 2011; 43: 879-882
        • Loveday C.
        • Turnbull C.
        • Ruark E.
        • Xicola R.M.
        • Ramsay E.
        • Hughes D.
        • et al.
        Germline RAD51C mutations confer susceptibility to ovarian cancer.
        Nat. Genet. 2012; 44 (author reply 6): 475-476
        • Rafnar T.
        • Gudbjartsson D.F.
        • Sulem P.
        • Jonasdottir A.
        • Sigurdsson A.
        • Jonasdottir A.
        • et al.
        Mutations in BRIP1 confer high risk of ovarian cancer.
        Nat. Genet. 2011; 43: 1104-1107
        • Ramus S.J.
        • Song H.
        • Dicks E.
        • Tyrer J.P.
        • Rosenthal A.N.
        • Intermaggio M.P.
        • et al.
        Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer.
        J. Natl. Cancer Inst. 2015; 107
        • Song H.
        • Dicks E.
        • Ramus S.J.
        • Tyrer J.P.
        • Intermaggio M.P.
        • Hayward J.
        • et al.
        Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population.
        J. Clin. Oncol. 2015; 33: 2901-2907
        • Norquist B.M.
        • Harrell M.I.
        • Brady M.F.
        • Walsh T.
        • Lee M.K.
        • Gulsuner S.
        • et al.
        Inherited mutations in women with ovarian carcinoma.
        JAMA Oncol. 2016; 2: 482-490
        • Dicks E.
        • Song H.
        • Ramus S.J.
        • Oudenhove E.
        • Tyrer J.P.
        • Intermaggio M.P.
        • et al.
        Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene.
        Oncotarget. 2017; (Advance Publication)
        • Drake A.C.
        • Campbell H.
        • Porteous M.E.
        • Dunlop M.G.
        The contribution of DNA mismatch repair gene defects to the burden of gynecological cancer.
        Int. J. Gynecol. Cancer. 2003; 13: 262-277
        • Ketabi Z.
        • Bartuma K.
        • Bernstein I.
        • Malander S.
        • Gronberg H.
        • Bjorck E.
        • et al.
        Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors.
        Gynecol Oncol. 2011; 121: 462-465
        • Pal T.
        • Akbari M.R.
        • Sun P.
        • Lee J.H.
        • Fulp J.
        • Thompson Z.
        • et al.
        Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.
        Br. J. Cancer. 2012; 107: 1783-1790
        • Minion L.E.
        • Dolinsky J.S.
        • Chase D.M.
        • Dunlop C.L.
        • Chao E.C.
        • Monk B.J.
        Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2.
        Gynecol Oncol. 2015; 137: 86-92
        • Ramsoekh D.
        • Wagner A.
        • van Leerdam M.E.
        • Dooijes D.
        • Tops C.M.
        • Steyerberg E.W.
        • et al.
        Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management.
        Hered. Cancer Clin. Pract. 2009; 7: 17
        • Bonadona V.
        • Bonaiti B.
        • Olschwang S.
        • Grandjouan S.
        • Huiart L.
        • Longy M.
        • et al.
        Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.
        Jama. 2011; 305: 2304-2310
        • Song H.
        • Ramus S.J.
        • Tyrer J.
        • Bolton K.L.
        • Gentry-Maharaj A.
        • Wozniak E.
        • et al.
        A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2.
        Nat. Genet. 2009; 41: 996-1000
        • Goode E.L.
        • Chenevix-Trench G.
        • Song H.
        • Ramus S.J.
        • Notaridou M.
        • Lawrenson K.
        • et al.
        A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24.
        Nat. Genet. 2010; 42: 874-879
        • Bolton K.L.
        • Tyrer J.
        • Song H.
        • Ramus S.J.
        • Notaridou M.
        • Jones C.
        • et al.
        Common variants at 19p13 are associated with susceptibility to ovarian cancer.
        Nat. Genet. 2010; 42: 880-884
        • Pharoah P.D.
        • Tsai Y.Y.
        • Ramus S.J.
        • Phelan C.M.
        • Goode E.L.
        • Lawrenson K.
        • et al.
        GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.
        Nat. Genet. 2013; 45 (70e1-2): 362-370
        • Bojesen S.E.
        • Pooley K.A.
        • Johnatty S.E.
        • Beesley J.
        • Michailidou K.
        • Tyrer J.P.
        • et al.
        Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
        Nat. Genet. 2013; 45 (84e1-2): 371-384
        • Shen H.
        • Fridley B.L.
        • Song H.
        • Lawrenson K.
        • Cunningham J.M.
        • Ramus S.J.
        • et al.
        Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer.
        Nat. Commun. 2013; 4: 1628
        • Permuth-Wey J.
        • Lawrenson K.
        • Shen H.C.
        • Velkova A.
        • Tyrer J.P.
        • Chen Z.
        • et al.
        Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31.
        Nat. Commun. 2013; 4: 1627
        • Chen K.
        • Ma H.
        • Li L.
        • Zang R.
        • Wang C.
        • Song F.
        • et al.
        Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women.
        Nat. Commun. 2014; 5: 4682
        • Kelemen L.E.
        • Lawrenson K.
        • Tyrer J.
        • Li Q.
        • Lee J.M.
        • Seo J.H.
        • et al.
        Genome-wide significant risk associations for mucinous ovarian carcinoma.
        Nat. Genet. 2015; 47: 888-897
        • Kar S.P.
        • Beesley J.
        • Amin Al Olama A.
        • Michailidou K.
        • Tyrer J.
        • Kote-Jarai Z.
        • et al.
        Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types.
        Cancer Discov. 2016; 6: 1052-1067
        • Phelan C.M.
        • Kuchenbaecker K.B.
        • Tyrer J.P.
        • Kar S.P.
        • Lawrenson K.
        • Winham S.J.
        • et al.
        Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.
        Nat. Genet. 2017;
        • Ghoussaini M.
        • Song H.
        • Koessler T.
        • Al Olama A.A.
        • Kote-Jarai Z.
        • Driver K.E.
        • et al.
        Multiple loci with different cancer specificities within the 8q24 gene desert.
        J. Natl. Cancer Inst. 2008; 100: 962-966
        • Kar S.P.B.J.
        Genome-wide meta-analyses of breast, ovarian and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types.
        Cancer Epidemiol. Biomarkers Prev. 2016;
        • Ross-Adams H.
        • Ball S.
        • Lawrenson K.
        • Halim S.
        • Russell R.
        • Wells C.
        • et al.
        HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer.
        Oncotarget. 2016; 7: 74734-74746
        • Lawrenson K.
        • Li Q.
        • Kar S.
        • Seo J.H.
        • Tyrer J.
        • Spindler T.J.
        • et al.
        Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.
        Nat. Commun. 2015; 6: 8234
        • Lawrenson K.
        • Kar S.
        • McCue K.
        • Kuchenbaeker K.
        • Michailidou K.
        • Tyrer J.
        • et al.
        Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.
        Nat. Commun. 2016; 712675
        • Cuellar-Partida G.
        • Lu Y.
        • Dixon S.C.
        • Fasching P.A.
        • Hein A.
        • Burghaus S.
        • et al.
        Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.
        Hum. Genet. 2016;
        • Pharoah P.D.
        • Easton D.F.
        • Stockton D.L.
        • Gayther S.
        • Ponder B.A.
        Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group.
        Cancer Res. 1999; 59: 868-871
        • Bolton K.L.
        • Chenevix-Trench G.
        • Goh C.
        • Sadetzki S.
        • Ramus S.J.
        • Karlan B.Y.
        • et al.
        Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer.
        JAMA. 2012; 307: 382-390
        • McLaughlin J.R.
        • Rosen B.
        • Moody J.
        • Pal T.
        • Fan I.
        • Shaw P.A.
        • et al.
        Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2.
        J. Natl. Cancer Inst. 2013; 105: 141-148
        • Cunningham J.M.
        • Cicek M.S.
        • Larson N.B.
        • Davila J.
        • Wang C.
        • Larson M.C.
        • et al.
        Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status.
        Sci. Rep. 2014; 4: 4026
        • Candido-dos-Reis F.J.
        • Song H.
        • Goode E.L.
        • Cunningham J.M.
        • Fridley B.L.
        • Larson M.C.
        • et al.
        Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.
        Clin. Cancer Res. 2015; 21: 652-657
        • Mann A.
        • Hogdall E.
        • Ramus S.J.
        • DiCioccio R.A.
        • Hogdall C.
        • Quaye L.
        • et al.
        Mismatch repair gene polymorphisms and survival in invasive ovarian cancer patients.
        Eur. J. Cancer. 2008; 44: 2259-2265
        • Quaye L.
        • Gayther S.A.
        • Ramus S.J.
        • Di Cioccio R.A.
        • McGuire V.
        • Hogdall E.
        • et al.
        The effects of common genetic variants in oncogenes on ovarian cancer survival.
        Clin. Cancer Res. 2008; 14: 5833-5839
        • Song H.
        • Hogdall E.
        • Ramus S.J.
        • Dicioccio R.A.
        • Hogdall C.
        • Quaye L.
        • et al.
        Effects of common germ-line genetic variation in cell cycle genes on ovarian cancer survival.
        Clin. Cancer Res. 2008; 14: 1090-1095
        • Quaye L.
        • Dafou D.
        • Ramus S.J.
        • Song H.
        • Gentry-Maharaj A.
        • Notaridou M.
        • et al.
        Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival.
        Hum. Mol. Genet. 2009; 18: 1869-1878
        • Johnatty S.E.
        • Tyrer J.P.
        • Kar S.
        • Beesley J.
        • Lu Y.
        • Gao B.
        • et al.
        Genome-wide analysis identifies novel loci associated with ovarian cancer outcomes: findings from the Ovarian Cancer Association Consortium.
        Clin. Cancer Res. 2015; 21: 5264-5276
        • Meehan R.S.
        • Chen A.P.
        New treatment option for ovarian cancer: PARP inhibitors.
        Gynecol. Oncol. Res. Pract. 2016; 3: 3
        • Papa A.
        • Caruso D.
        • Strudel M.
        • Tomao S.
        • Tomao F.
        Update on poly-ADP-ribose polymerase inhibition for ovarian cancer treatment.
        J. Transl. Med. 2016; 14: 267
        • Reiss K.A.
        • Herman J.M.
        • Armstrong D.
        • Zahurak M.
        • Fyles A.
        • Brade A.
        • et al.
        A final report of a phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy (LDFWAR) in patients with advanced solid malignancies and peritoneal carcinomatosis with a dose escalation in ovarian and fallopian tube cancers.
        Gynecol. Oncol. 2017; 144: 486-490
        • Mirza M.R.
        • Monk B.J.
        • Herrstedt J.
        • Oza A.M.
        • Mahner S.
        • Redondo A.
        • et al.
        Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.
        N. Engl. J. Med. 2016; 375: 2154-2164
        • Ledermann J.A.
        • Harter P.
        • Gourley C.
        • Friedlander M.
        • Vergote I.
        • Rustin G.
        • et al.
        Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial.
        Lancet Oncol. 2016; 17: 1579-1589
        • Kaufman B.
        • Shapira-Frommer R.
        • Schmutzler R.K.
        • Audeh M.W.
        • Friedlander M.
        • Balmana J.
        • et al.
        Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
        J. Clin. Oncol. 2015; 33: 244-250
        • Konecny G.E.
        • Kristeleit R.S.P.A.R.P.
        inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions.
        Br. J. Cancer. 2016; 115: 1157-1173
        • George A.
        • Riddell D.
        • Seal S.
        • Talukdar S.
        • Mahamdallie S.
        • Ruark E.
        • et al.
        Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients.
        Sci. Rep. 2016; 629506
        • Hall M.J.
        • Reid J.E.
        • Burbidge L.A.
        • Pruss D.
        • Deffenbaugh A.M.
        • Frye C.
        • et al.
        BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer.
        Cancer. 2009; 115: 2222-2233
        • Easton D.F.
        • Pharoah P.D.
        • Foulkes W.D.
        ClinGen and genetic testing.
        N. Engl. J. Med. 2015; 373: 1378
        • Daly M.B.
        • Pilarski R.
        • Berry M.
        • Buys S.S.
        • Farmer M.
        • Friedman S.
        • et al.
        NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017.
        J. Natl. Compr. Cancer Netw. 2017; 15: 9-20
        • Tung N.
        • Domchek S.M.
        • Stadler Z.
        • Nathanson K.L.
        • Couch F.
        • Garber J.E.
        • et al.
        Counselling framework for moderate-penetrance cancer-susceptibility mutations.
        Nat. Rev. Clin. Oncol. 2016; 13: 581-588
        • Lek M.
        • Karczewski K.J.
        • Minikel E.V.
        • Samocha K.E.
        • Banks E.
        • Fennell T.
        • et al.
        Analysis of protein-coding genetic variation in 60,706 humans.
        Nature. 2016; 536: 285-291
        • Meeks H.D.
        • Song H.
        • Michailidou K.
        • Bolla M.K.
        • Dennis J.
        • Wang Q.
        • et al.
        BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers.
        J. Natl. Cancer Inst. 2016; 108
        • Michailidou K.
        • Hall P.
        • Gonzalez-Neira A.
        • Ghoussaini M.
        • Dennis J.
        • Milne R.L.
        • et al.
        Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
        Nat. Genet. 2013; 45 (61e1-2): 353-361