Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
Authors: DeVries Amber A , Dennis Joe , Tyrer Jonathan P , Peng Pei-Chen , Coetzee Simon G , Reyes Alberto L , Plummer Jasmine T , Davis Brian D , Chen Stephanie S , Dezem Felipe Segato , Aben Katja K H , Anton-Culver Hoda , Antonenkova Natalia N , Beckmann Matthias W , Beeghly-Fadiel Alicia , Berchuck Andrew , Bogdanova Natalia V , Bogdanova-Markov Nadja , Brenton James D , Butzow Ralf , Campbell Ian , Chang-Claude Jenny , Chenevix-Trench Georgia , Cook Linda S , DeFazio Anna , Doherty Jennifer A , Dörk Thilo , Eccles Diana M , Eliassen A Heather , Fasching Peter A , Fortner Renée T , Giles Graham G , Goode Ellen L , Goodman Marc T , Gronwald Jacek ,   OPAL Study Group, Webb P , DeFazio A , Friedlander M , Obermair A , Grant P , Nagle C , Beesley V , Chevenix-Trench G , Bowtell D , Blomfield P , Brand A , Davis A , Leung Y , Nicklin J , Quinn M , Livingstone K , O'Neill H , Williams M , Black A , Hadley A , Glasgow A , Garrett A , Rao A , Shannon C , Steer C , Allen D , Neesham D , Otton G , Au-Yeung G , Goss G , Wain G , Gard G , Robertson G , Lombard J , Tan J , McNeilage J , Power J , Coward J , Miller J , Carter J , Lamont J , Wong K M , Reid K , Perrin L , Milishkin L , Nascimento M , Buck M , Bunting M , Harrison M , Chetty N , Hacker N , McNally O , Harnett P , Beale P , Awad R , Mohan R , Farrell R , McIntosh R , Rome R , Sayer R , Houghton R , Hogg R , Land R , Baron-Hay S , Paramasivum S , Pather S , Hyde S , Salfinger S , Valmadre S , Jobling T , Manolitsas T , Bonaventura T , Arora V ,   AOCS Group, Bowtell D , Chenevix-Trench G , Green A , Webb P , DeFazio A , Gertig D , Traficante N , Fereday S , Moore S , Hung J , Harrap K , Sadkowsky T , Pandeya N , Malt M , Robertson R , Bergh T Vanden , Jones M , McKenzie P , Maidens J , Nattress K , Chiew Y E , Stenlake A , Sullivan H , Alexander B , Ashover P , Brown S , Corrish T , Green L , Jackman L , Ferguson K , Martin K , Martyn A , Ranieri B , White J , Jayde V , Bowes L , Mamers P , Galletta L , Giles D , Hendley J , Alsop K , Schmidt T , Shirley H , Ball C , Young C , Viduka S , Tran H , Bilic S , Glavinas L , Brooks J , Stuart-Harris R , Kirsten F , Rutovitz J , Clingan P , Glasgow A , Proietto A , Braye S , Otton G , Shannon J , Bonaventura T , Stewart J , Begbie S , Håkansson Niclas , Hildebrandt Michelle A T , Huff Chad , Huntsman David G , Jensen Allan , Kar Siddhartha , Karlan Beth Y , Khusnutdinova Elza K , Kiemeney Lambertus A , Kjaer Susanne K , Kupryjanczyk Jolanta , Labrie Marilyne , Lambrechts Diether , Le Nhu D , Lubiński Jan , May Taymaa , Menon Usha , Milne Roger L , Modugno Francesmary , Monteiro Alvaro N , Moysich Kirsten B , Odunsi Kunle , Olsson Håkan , Pearce Celeste L , Pejovic Tanja , Ramus Susan J , Riboli Elio , Riggan Marjorie J , Romieu Isabelle , Sandler Dale P , Schildkraut Joellen M , Setiawan V Wendy , Sieh Weiva , Song Honglin , Sutphen Rebecca , Terry Kathryn L , Thompson Pamela J , Titus Linda , Tworoger Shelley S , Van Nieuwenhuysen Els , Edwards Digna Velez , Webb Penelope M , Wentzensen Nicolas , Whittemore Alice S , Wolk Alicja , Wu Anna H , Ziogas Argyrios , Freedman Matthew L , Lawrenson Kate , Pharoah Paul D P , Easton Douglas F , Gayther Simon A , Jones Michelle R 
Published: October 2022

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 &lt; .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P &lt; .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.