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

作者：Amber A DeVries, Joe Dennis, Jonathan P. Tyrer, Pei-Chen Peng, Simon G. Coetzee, Alberto Luiz P. Reyes, Jasmine Plummer, Brian D Davis, Stephanie S. Chen, Felipe Segato Dezem, Katja K.H. Aben, Hoda Anton‐Culver, Natalia Antonenkova, Matthias W. Beckmann, Alicia C. Beeghly-Fadiel, Andrew Berchuck, Natalia Bogdanova, Nadja Bogdanova-Markov, James D. Brenton, Ralf C. Bützow, Ian Campbell, Jenny C. Chang-Claude, Georgia Chenevix‐Trench, Linda S. Cook, Anna DeFazio, Jennifer A. Doherty, Thilo Dörk, Diana M Eccles, A. Heather Eliassen, Peter Andreas Fasching, Renée T. Fortner, Graham G. Giles, Ellen L. Goode, Marc T. Goodman, Jacek Gronwald, OPAL Study Group, P Webb, Anna DeFazio, Michael Leonard Friedlander, Andreas Obermair, Peter Grant, C.A. Nagle, Vanessa L. Beesley, G Chevenix-Trench, D Bowtell, Penny I. Blomfield, Alison H. Brand, Alison J. Davis, Yee Chit Leung, James Nicklin, Michael A. Quinn, Karen Livingstone, Helen C. O’Neill, Marie Williams, Amanda Black, Alison Maree Hadley, Anum Azam Glasgow, Ashley L. Garrett, Archana Rao, Colleen Shannon, Christopher Steer, Deborah Emma Allen, Deborah E. Neesham, Geoffrey R. Otton, George Au‐Yeung, Geraldine Goss, Gerard Wain, Grace Gard, G S M Robertson, Janine Margaret Lombard, Joanne Yue-Ai Tan, Jane McNeilage, J. Power, Jermaine I Coward, Jessica Anne Miller, Jonathan R. Carter, John V. Lamont, Kit Man Wong, Kate Reid, Lewis C Perrin, L Milishkin, Moysés Nascimento, Martin Buck, Michael W Bunting, Michelle Harrison, Naven Chetty, Neville F. Hacker, Orla McNally, Paul R. Harnett, Philip James Beale, Reda Awad, Rahul R. Mohan, Rhonda Farrell, Rachel L. McIntosh, Robert M Rome, R. Drew Sayer, Roger S. Houghton, Russell Hogg, R. Land, Sally E. Baron-Hay, S Paramasivum, Selvan Pather, Samuel M. Hyde, Stuart G. Salfinger, Susan Valmadre, Thomas W. Jobling, Tom Manolitsas, T Bonaventura, Vivek Arora, AOCS Group, D Bowtell, Georgia Chenevix‐Trench, A Green, P Webb, Anna DeFazio, Dorota M. Gertig, Nadia Traficante, Sián Fereday, S. Moore, Jillian A. Hung, Karen L. Harrap, T. Sadkowsky, Nirmala Pandeya, Maryrose K. Malt, R. Paul Robertson, T. Vanden Bergh, Michelle R. Jones, Patrick McKenzie, John Maidens, K. Nattress, Yoke-Eng Chiew, Annie Stenlake, Helen T. Sullivan, Brian Michael Alexander, P. Ashover, Susan Drucker Brown, T. Corrish, Laura Elizabeth Green, Louisa Jackman, Kaltin Ferguson, Kara L. Martin, Amanda C. Martyn, Brigida Ranieri, Jonathan White, Victoria Jayde, Laura Bowes, Pamela M. Mamers, Laura Galletta, Daniel A. Giles, Joy Hendley, Kathryn Alsop, Tannin A. Schmidt, H. Shirley, C. Ball, Christian D. Young, S. Viduka, Huyen Anh Tran, Sanela Bilic, Lydia Glavinas, Jacqueline D. Brooks, R. Stuart‐Harris, Fred Kirsten, Jay Rutovitz, P. Clingan, Anum Azam Glasgow, Anthony M. Proietto, Stephen G. Braye, Geoffrey R. Otton, J. Shannon, T Bonaventura, James Stewart, Stephen D. Begbie, Niclas Håkansson, Michelle A.T. Hildebrandt, Chad Daniel Huff, David G. Huntsman, Allan Jensen, Siddhartha Kar, Beth Y. Karlan, Э. К. Хуснутдинова, Lambertus A.L.M. Kiemeney, Susanne K. Kjær, Jolanta Kupryjańczyk, Marilyne Labrie, Diether Lambrechts, Nhu D. Le, Jan Lubiński, Taymaa May, Usha Menon, Roger Laughlin Milne, Francesmary Modugno, Álvaro N.A. Monteiro, Kirsten B. Moysich, Kunle O. Odunsi, Hakan Lars Olsson, Celeste Leigh Pearce, Tanja B. Pejovic, Susan J. Ramus, Elio Ríboli, Marjorie J. Riggan, Isabelle Romieu, Dale P. Sandler, Joellen M. Schildkraut, Veronica Wendy Setiawan, Weiva Sieh, Honglin Song, Rebecca Sutphen, Kathryn L. Terry, Pamela J. Thompson, Linda J Titus, Shelley S. Tworoger, Els Van Nieuwenhuysen, Digna R. Velez Edwards, Penelope M. Webb, Nicolas Wentzensen, Alice S. Whittemore, Alicja Wolk, Anna H. Wu, Argyrios Ziogas, Matthew L. Freedman, Kate Lawrenson, Paul D.P. Pharoah, Douglas F. Easton, Simon A. Gayther, Michelle R. Jones · 发表于：JNCI Journal of the National Cancer Institute · 年份：2022 · DOI：10.1093/jnci/djac160 · 被引用次数：13 · 研究领域：Genomic variations and chromosomal abnormalities、BRCA gene mutations in cancer、Genetic Associations and Epidemiology

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 diseas...