TY - JOUR
T1 - Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
AU - GEMO Study Collaborators
AU - EMBRACE Collaborators
AU - SWE-BRCA Investigators
AU - KConFab investigators
AU - HEBON Investigators
AU - Hakkaart, Christopher
AU - Pearson, John F.
AU - Marquart, Louise
AU - Dennis, Joe
AU - Wiggins, George A.R.
AU - Barnes, Daniel R.
AU - Robinson, Bridget A.
AU - Mace, Peter D.
AU - Aittomäki, Kristiina
AU - Andrulis, Irene L.
AU - Arun, Banu K.
AU - Azzollini, Jacopo
AU - Balmaña, Judith
AU - Barkardottir, Rosa B.
AU - Belhadj, Sami
AU - Berger, Lieke
AU - Blok, Marinus J.
AU - Boonen, Susanne E.
AU - Borde, Julika
AU - Bradbury, Angela R.
AU - Brunet, Joan
AU - Buys, Saundra S.
AU - Caligo, Maria A.
AU - Campbell, Ian
AU - Chung, Wendy K.
AU - Claes, Kathleen B.M.
AU - Collonge-Rame, Marie Agnès
AU - Cook, Jackie
AU - Cosgrove, Casey
AU - Couch, Fergus J.
AU - Daly, Mary B.
AU - Dandiker, Sita
AU - Davidson, Rosemarie
AU - de la Hoya, Miguel
AU - de Putter, Robin
AU - Delnatte, Capucine
AU - Dhawan, Mallika
AU - Diez, Orland
AU - Ding, Yuan Chun
AU - Domchek, Susan M.
AU - Donaldson, Alan
AU - Eason, Jacqueline
AU - Easton, Douglas F.
AU - Ehrencrona, Hans
AU - Engel, Christoph
AU - Evans, D. Gareth
AU - Faust, Ulrike
AU - Feliubadaló, Lidia
AU - Fostira, Florentia
AU - Friedman, Eitan
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-022-03978-6
DO - 10.1038/s42003-022-03978-6
M3 - Article
C2 - 36203093
AN - SCOPUS:85139349547
SN - 2399-3642
VL - 5
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 1061
ER -