Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Devries AA, Dennis J, Tyrer JP, Peng PC, Coetzee SG, Reyes AL, Plummer JT, Davis BD, Chen SS, Dezem FS, Aben KKH, Anton-Culver H, Antonenkova NN, Beckmann M, Beeghly-Fadiel A, Berchuck A, Bogdanova N, Bogdanova-Markov N, Brenton JD, Butzow R, Campbell I, Chang-Claude J, Chenevix-Trench G, Cook LS, Defazio A, Doherty JA, Dork T, Eccles DM, Eliassen AH, Fasching P, Fortner RT, Giles GG, Goode EL, Goodman MT, Gronwald J, Hakansson N, Hildebrandt MAT, Huff C, Huntsman DG, Jensen A, Kar S, Karlan BY, Khusnutdinova EK, Kiemeney LA, Kjaer SK, Kupryjanczyk J, Labrie M, Lambrechts D, Le ND, Lubinski J, May T, Menon U, Milne RL, Modugno F, Monteiro AN, Moysich KB, Odunsi K, Olsson H, Pearce CL, Pejovic T, Ramus SJ, Riboli E, Riggan MJ, Romieu I, Sandler DP, Schildkraut JM, Setiawan VW, Sieh W, Song H, Sutphen R, Terry KL, Thompson PJ, Titus L, Tworoger SS, Van Nieuwenhuysen E, Edwards DV, Webb PM, Wentzensen N, Whittemore AS, Wolk A, Wu AH, Ziogas A, Freedman ML, Lawrenson K, Pharoah PDP, Easton DF, Gayther SA, Jones MR (2022)

Publication Type: Journal article

Publication year: 2022


DOI: 10.1093/jnci/djac160


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 (P-EOC = 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 (P-HGSOC = 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.

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Involved external institutions

University of Bristol GB United Kingdom (GB) University of California Irvine US United States (USA) (US) Cedars-Sinai Medical Center US United States (USA) (US) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology BY Belarus (BY) University of Cambridge GB United Kingdom (GB) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Vanderbilt University US United States (USA) (US) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) University of Texas MD Anderson Cancer Center US United States (USA) (US) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) PL Poland (PL) Karolinska Institute SE Sweden (SE) University of British Columbia CA Canada (CA) Mayo Clinic US United States (USA) (US) Danish Cancer Society Research Center DK Denmark (DK) University of California Los Angeles (UCLA) US United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) University of Southampton GB United Kingdom (GB) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) University of Utah US United States (USA) (US) University of Colorado System US United States (USA) (US) University of Michigan US United States (USA) (US) BC Cancer CA Canada (CA) University of Pittsburgh US United States (USA) (US) Imperial College London / The Imperial College of Science, Technology and Medicine GB United Kingdom (GB) National Cancer Institute (NCI) US United States (USA) (US) Icahn School of Medicine at Mount Sinai US United States (USA) (US) Roswell Park Cancer Institute US United States (USA) (US) World Health Organization CH Switzerland (CH) Oregon Health and Science University (OSHU) US United States (USA) (US) University of Chicago US United States (USA) (US) University of Southern Maine US United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie PL Poland (PL) University of New South Wales (UNSW) AU Australia (AU) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) University College London (UCL) GB United Kingdom (GB) Lund University / Lunds universitet SE Sweden (SE) Brigham and Women's Hospital (BWH) US United States (USA) (US) Emory University US United States (USA) (US) Stanford University US United States (USA) (US) Harvard University US United States (USA) (US) Helsingin yliopisto / University of Helsinki FI Finland (FI) Westmead Institute for Medical Research AU Australia (AU) Dana–Farber Cancer Institute US United States (USA) (US) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) BE Belgium (BE) Russian Academy of Sciences / Росси́йская акаде́мия нау́к (RAS) RU Russian Federation (RU) Peter MacCallum Cancer Centre AU Australia (AU) University of Southern California (USC) US United States (USA) (US) University of South Florida (USF) US United States (USA) (US) National Institute of Environmental Health Sciences (NIEHS) US United States (USA) (US) Cancer Council Victoria AU Australia (AU) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite


Devries, A.A., Dennis, J., Tyrer, J.P., Peng, P.-C., Coetzee, S.G., Reyes, A.L.,... Jones, M.R. (2022). Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci. Journal of the National Cancer Institute.


Devries, Amber A., et al. "Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci." Journal of the National Cancer Institute (2022).

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