1. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.
- Author
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Hakkaart C, Pearson JF, Marquart L, Dennis J, Wiggins GAR, Barnes DR, Robinson BA, Mace PD, Aittomäki K, Andrulis IL, Arun BK, Azzollini J, Balmaña J, Barkardottir RB, Belhadj S, Berger L, Blok MJ, Boonen SE, Borde J, Bradbury AR, Brunet J, Buys SS, Caligo MA, Campbell I, Chung WK, Claes KBM, Collonge-Rame MA, Cook J, Cosgrove C, Couch FJ, Daly MB, Dandiker S, Davidson R, de la Hoya M, de Putter R, Delnatte C, Dhawan M, Diez O, Ding YC, Domchek SM, Donaldson A, Eason J, Easton DF, Ehrencrona H, Engel C, Evans DG, Faust U, Feliubadaló L, Fostira F, Friedman E, Frone M, Frost D, Garber J, Gayther SA, Gehrig A, Gesta P, Godwin AK, Goldgar DE, Greene MH, Hahnen E, Hake CR, Hamann U, Hansen TVO, Hauke J, Hentschel J, Herold N, Honisch E, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James PA, Janavicius R, John EM, Joseph V, Karlan BY, Kemp Z, Kirk J, Konstantopoulou I, Koudijs M, Kwong A, Laitman Y, Lalloo F, Lasset C, Lautrup C, Lazaro C, Legrand C, Leslie G, Lesueur F, Mai PL, Manoukian S, Mari V, Martens JWM, McGuffog L, Mebirouk N, Meindl A, Miller A, Montagna M, Moserle L, Mouret-Fourme E, Musgrave H, Nambot S, Nathanson KL, Neuhausen SL, Nevanlinna H, Yie JNY, Nguyen-Dumont T, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Osorio A, Ott CE, Park SK, Parsons MT, Pedersen IS, Peixoto A, Perez-Segura P, Peterlongo P, Pocza T, Radice P, Ramser J, Rantala J, Rodriguez GC, Rønlund K, Rosenberg EH, Rossing M, Schmutzler RK, Shah PD, Sharif S, Sharma P, Side LE, Simard J, Singer CF, Snape K, Steinemann D, Stoppa-Lyonnet D, Sutter C, Tan YY, Teixeira MR, Teo SH, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Trainer AH, Tripathi V, Tung N, van Engelen K, van Rensburg EJ, Vega A, Viel A, Walker L, Weitzel JN, Wevers MR, Chenevix-Trench G, Spurdle AB, Antoniou AC, and Walker LC
- Subjects
- BRCA1 Protein genetics, BRCA2 Protein genetics, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Heterozygote, Humans, RNA, Messenger, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers., (© 2022. The Author(s).)
- Published
- 2022
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