Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
Abstract
Background
Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.
Methods
Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.
Results
We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.
Conclusions
CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
Institutions
University Of CambridgeSt Jude Childrens Research HospitalUniversity Of California IrvinePeter Maccallum Cancer CentreQimr Berghofer Medical Research InstituteBrigham And Womens HospitalThe University Of QueenslandCedars Sinai Medical CenterDanish Arctic InstituteUniversity College LondonImperial College LondonThe University Of Texas Md Anderson Cancer CenterDivision Of Cancer Epidemiology And GeneticsKarolinska Institutet
Authors
Funding
Medical Research Council Grant MR/M012190/1Life Course Cancer Epidemiology Cohort in WomenHereditary Breast Cancer: Genetic and Molecular StudiesOVARIAN CANCER RISK AND SURVIVAL IN BRCA CARRIERSDana-Farber/Harvard Cancer Center Ovarian Cancer SPOREWellcome Trust Grant 076113NCATS NIH HHS Grant ULTR000445The Mitochondrial Genome and Ovarian Cancer RiskCancer Research UK Grant C490/A10119 C490/A10124Medical Research Council Grant 1000143NIH Grant R01-CA54419Cancer Research UK Grant C8221/A19170SURVEILLANCE EPIDEMIOLOGY & END RESULTS PROGRAMProject 1Graduate Program in Biomedical Sciences and Translational MedicineUS National Institutes of Health Grant CA1X01HG007491-01Environmental and Genetic Risk Factors For Breast Cancer: The Sister StudyEnvironmental and Genetic Risk Factors For Breast Cancer: The Sister StudyCore A: Biospecimen and High-Dimensional Data Management CoreMedical Research Council Grant MR/N003284/1Premenopausal Hormone Levels and Risk of Breast CancerPopulation-Based Analysis of Ovarian Cancer BiomarkersGeneral Clinical Research CenterInflammation and Ovarian CancerCancer Research Career Enhancement and Related ActivitiesThe Progesterone Receptor Gene and Ovarian Cancer RiskCollaborative Genetic Study of Ovarian Cancer RiskLife Course Cancer Epidemiology Cohort in WomenDepartment of Health FundingGenetic Susceptibility And The Environment In Cancer RiskAutomated Storage and Retrieval of Biological SystemsMedical Research Council Grant G1000143Graduate Program in Biomedical Sciences and Translational MedicineOVARIAN CANCER RISK AND SURVIVAL IN BRCA CARRIERSGenetic Variation in the NF-kappaB Pathway and Ovarian Cancer EtiologyCancer Research UK Grant 14136Worldwide Cancer Research FundingCancer Research Training and Education CoordinationMedical Research Council (MRC) Grant MC_UU_00004/01Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)Medical Research Council Grant G0401527Medical Research Council Grant MR_UU_12023Ovarian Cancer and Gonadotropin SignalingNational Cancer Institute Grant UM1 CA186107Genes, Hormones & Environment in an Ovarian Cancer ModelGenetic Variation in the NF-kappaB Pathway and Ovarian Cancer EtiologyCancer Risk Assessment, Early Detection, and Interception Research ProgramThe Molecular Epidemiology Of Ovarian CancerNHGRI NIH HHS FundingNCI NIH HHS Grant R01- CA61107Relating Molecular Subgroups of Endometriosis-Associated Ovarian Cancers to Survival and RiskNational Institutes of Health Grant R01-CA58598Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)Hormone Therapy and Risk of Ovarian CancerSURVEILLANCE EPIDEMIOLOGY AND END RESULTSBiochemical Markers in the nurses' Health Study CohortBreast Cancer Now FundingMitochondrial DNA and Ovarian Cancer Risk and SurvivalHereditary Breast Cancer: Genetic and Molecular StudiesCancer Research UK Grant C570/A16491NIH Grant R01-CA76016NIH HHS Grant R01-CA106414-A2World Health Organization Grant 001Project 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian CancerRegulatory T Cell Function in Ovarian CancerWellcome Trust Grant 209057National Institute of General Medical Sciences FundingCSMC Precision Health Initiative FundingTell Every Amazing Lady About Ovarian Cancer Louisa M. McGregor Ovarian Cancer Foundation FundingOvarian Cancer Research Fund thanks Grant PPD/RPCI.07National Cancer Institute FundingNational Human Genome Research Institute FundingFollow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)The Mitochondrial Genome and Ovarian Cancer RiskCollaborative Genetic Study of Ovarian Cancer RiskCanadian Institutes of Health Research Grant MOP-86727Ovarian Cancer Research Fund FundingEuropean Commission's Seventh Framework Programme Grant 223175 - HEALTH-F2-2009-223175Army Medical Research and Materiel Command Grant DAMD17-01-1-0729National Health & Medical Research Council of Australia Grant 199600National Health & Medical Research Council of Australia Grant 400413National Health & Medical Research Council of Australia Grant 400281Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania; and Cancer Foundation of Western Australia FundingOvarian Cancer Australia FundingPeter MacCallum Foundation FundingUniversity of Erlangen-Nuremberg FundingNational Kankerplan FundingBreast Cancer Now, Institute of Cancer Research FundingNational Institutes of Health FundingNational Center for Advancing Translational Sciences Grant ULTR000445Automated Storage and Retrieval of Biological SystemsEuropean Commission FundingInternational Agency for Research on Cancer FundingDanish Cancer Society Grant EMC 2014-6699Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale FundingInstitut National de la Sant? et de la Recherche M?dicale FundingGerman Cancer Aid, German Cancer Research Center FundingFederal Ministry of Education and Research FundingHellenic Health Foundation FundingAssociazione Italiana per la Ricerca sul Cancro-AIRC-Italy FundingNational Research Council FundingDutch Ministry of Public Health, Welfare and Sports FundingNetherlands Cancer Registry FundingLK Research Funds FundingDutch Prevention Funds FundingWorld Cancer Research Fund FundingNordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health FundingHealth Research Fund Grant PI13/00061Health Research Fund Grant PI13/01162Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra Grant RD06/0020Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten FundingGerman Federal Ministry of Education and Research, Programme of Clinical Biomedical Research FundingGerman Cancer Research Center FundingIn vitro and In Vivo screening of chemopreventive agentsCancer Genetic Network (CGN)Rudolf Bartling Foundation FundingHelsinki University Hospital Research Fund FundingUniversity of Pittsburgh School of Medicine Dean's Faculty Advancement Award FundingUS Department of Defense Grant DAMD17-02-1-0669National Cancer Institute Grant R01-CA95023Project 1National Cancer Institute Grant MO1-RR000056Regulatory T Cell Function in Ovarian CancerSwedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation FundingDanish Cancer Society, Copenhagen Grant 94 222 52National Institutes of Health (NIH) Grant P30-CA15083Project 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian CancerMayo Foundation FundingMinnesota Ovarian Cancer Alliance FundingFred C and Katherine B Andersen Foundation FundingVicHealth and Cancer Council Victoria, Cancer Council Victoria FundingNational Health and Medical Research Council of Australia FundingNHMRC Grant 209057NHMRC Grant 251533NHMRC Grant 396414NHMRC Grant 504715DOD Ovarian Cancer Research Program Grant W81XWH-07-0449Moffitt Cancer Center FundingMerck Pharmaceuticals FundingDepartment of Defense Grant DAMD17-02-1-0666Dana-Farber/Harvard Cancer Center Ovarian Cancer SPOREU.S. Department of Defense (United States Department of Defense) Grant W81XWH-10-1-02802Department of Defense Grant UM1 CA186107Department of Defense Grant P01 CA87969Department of Defense Grant R01 CA49449Department of Defense Grant R01-CA67262Department of Defense Grant UM1 CA176726Radboud University Medical Centre FundingUK National Institute for Health Research Biomedical Research Centres at the University of Cambridge FundingEnvironmental and Genetic Risk Factors For Breast Cancer: The Sister StudyGenetic Susceptibility And The Environment In Cancer RiskThe Swedish Cancer Foundation Fundingthe Swedish Research Council Grant VR 2017-00644National Institutes of Health Grant R01-CA106414-A2American Cancer Society Grant CRTG-00-196-01-CCEDepartment of Defense Grant DAMD17-98-1-8659Celma Mastry Ovarian Cancer Foundation FundingLon V Smith Foundation Grant LVS-39420The Eve Appeal FundingNational Institute for Health Research University College London Hospitals Biomedical Research Centre Grant MR_UU_12023National Institute for Health Research University College London Hospitals Biomedical Research Centre Grant P01CA17054National Institute for Health Research University College London Hospitals Biomedical Research Centre Grant P30CA14089National Institute for Health Research University College London Hospitals Biomedical Research Centre Grant R01CA61132National Institute for Health Research University College London Hospitals Biomedical Research Centre Grant N01PC67010The Progesterone Receptor Gene and Ovarian Cancer RiskOvarian Cancer and Gonadotropin SignalingSURVEILLANCE EPIDEMIOLOGY AND END RESULTSCalifornia Cancer Research Program Grant 00-01389 V-20170, 2II0200National Science Centre FundingNIH Funding