TY - JOUR
T1 - BRCA2 hypomorphic missense variants confer moderate risks of breast cancer
AU - kConFab/AOCS Investigators
AU - NBCS Collaborators
AU - Shimelis, Hermela
AU - Mesman, Romy L.S.
AU - Von Nicolai, Catharina
AU - Ehlen, Asa
AU - Guidugli, Lucia
AU - Martin, Charlotte
AU - Calléja, Fabienne M.G.R.
AU - Meeks, Huong
AU - Hallberg, Emily
AU - Hinton, Jamie
AU - Lilyquist, Jenna
AU - Hu, Chunling
AU - Aalfs, Cora M.
AU - Aittomäki, Kristiina
AU - Andrulis, Irene
AU - Anton-Culver, Hoda
AU - Arndt, Volker
AU - Beckmann, Matthias W.
AU - Benitez, Javier
AU - Bogdanova, Natalia V.
AU - Bojesen, Stig E.
AU - Bolla, Manjeet K.
AU - Borresen-Dale, Anne Lise
AU - Brauch, Hiltrud
AU - Brennan, Paul
AU - Brenner, Hermann
AU - Broeks, Annegien
AU - Brouwers, Barbara
AU - Brüning, Thomas
AU - Burwinkel, Barbara
AU - Chang-Claude, Jenny
AU - Chenevix-Trench, Georgia
AU - Cheng, Ching Yu
AU - Choi, Ji Yeob
AU - Collée, J. Margriet
AU - Cox, Angela
AU - Cross, Simon S.
AU - Czene, Kamila
AU - Darabi, Hatef
AU - Dennis, Joe
AU - Dörk, Thilo
AU - Dos-Santos-Silva, Isabel
AU - Dunning, Alison M.
AU - Fasching, Peter A.
AU - Figueroa, Jonine
AU - Flyger, Henrik
AU - García-Closas, Montserrat
AU - Olson, Janet E.
AU - Slager, Susan
AU - Couch, Fergus J.
N1 - Funding Information:
We thank Shyam Sharan for the Pl2F7 conditional mBrca2 knockout mES cell line and Maria Jasin for the DR-GFP-targeting construct. This work was supported in part by NIH grants CA116167, CA176785, CA192393, an NIH specialized program of research excellence (SPORE) in breast cancer to the Mayo Clinic (P50 CA116201), the Breast Cancer Research Foundation (to F.C. Couch), the ATIP-AVENIR CNRS/INSERM Young Investigator grant 201201, EC-Marie Curie Career Integration grant CIG293444, Institute National du CancerINCa-DGOS-8706 (to A. Carreira), the Dutch Cancer Society KWF (UL2012-5649 to M.P.G. Vreeswijk), the Australian National Health and Medical Research Council (ID#1010719), and The Cancer Council Queensland (ID#1086286 to A. Spurdle). BCAC data management was funded by Cancer Research UK (C1287/A10118 and C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175 to D.F. Easton). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no. 223175 (COGS; HEALTH-F2-2009-223175 to P. Hall), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 to D.F. Easton), the NIH (CA128978 to F.J. Couch), and Post-Cancer GWAS initiative (1U19 CA148537, C.A. Haiman; 1U19 CA148065, D.F. Easton; and 1U19 CA148112 - the GAME-ON initiative to T.A. Sellers), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (to I. Andrulis), and the Breast Cancer Research Foundation (to F.J. Couch). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.
AB - Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.
UR - http://www.scopus.com/inward/record.url?scp=85020735683&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020735683&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-2568
DO - 10.1158/0008-5472.CAN-16-2568
M3 - Article
C2 - 28283652
AN - SCOPUS:85020735683
VL - 77
SP - 2789
EP - 2799
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -