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

Journal

DOI: 10.1093/jnci/djac160

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 (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.

Authors with CRIS profile

Involved external institutions

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

How to cite

APA:

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. https://doi.org/10.1093/jnci/djac160

MLA:

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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