Article
BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer
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- (1) Mayo Clinic, grid.66875.3a
- (2) Leiden University Medical Center, grid.10419.3d
- (3) Genotoxic Stress and Cancer, grid.493838.d
- (4) University of Chicago, grid.170205.1
- (5) Institute Curie, grid.418596.7
- (6) University of Utah, grid.223827.e
- (7) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- (8) University of Toronto, grid.17063.33
- (9) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
- (10) University of California, Irvine, grid.266093.8
- (11) German Cancer Research Center, grid.7497.d
- (12) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- (13) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
- (14) Spanish National Cancer Research Centre, grid.7719.8
- (15) Hannover Medical School, grid.10423.34
- (16) Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- (17) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- (18) University of Copenhagen, grid.5254.6, KU
- (19) University of Cambridge, grid.5335.0
- (20) K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- (21) Oslo University Hospital, grid.55325.34
- (22) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
- (23) University of Tübingen, grid.10392.39
- (24) International Agency For Research On Cancer, grid.17703.32
- (25) Antoni van Leeuwenhoek Hospital, grid.430814.a
- (26) Universitair Ziekenhuis Leuven, grid.410569.f
- (27) Ruhr University Bochum, grid.5570.7
- (28) Heidelberg University, grid.7700.0
- (29) University Cancer Center Hamburg, grid.412315.0
- (30) QIMR Berghofer Medical Research Institute, grid.1049.c
- (31) National University of Singapore, grid.4280.e
- (32) Seoul National University, grid.31501.36
- (33) Erasmus University Medical Center, grid.5645.2
- (34) University of Sheffield, grid.11835.3e
- (35) Karolinska Institute, grid.4714.6
- (36) London School of Hygiene & Tropical Medicine, grid.8991.9
- (37) University of California, Los Angeles, grid.19006.3e
- (38) University of Edinburgh, grid.4305.2
- (39) National Cancer Institute, grid.48336.3a
- (40) Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- (41) University of Melbourne, grid.1008.9
- (42) Cancer Council Victoria, grid.3263.4
- (43) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
- (44) University of Southern California, grid.42505.36
- (45) National University Health System, grid.410759.e
- (46) Aichi Cancer Center, grid.410800.d
- (47) Nagoya University, grid.27476.30
- (48) Pomeranian Medical University, grid.107950.a
- (49) Kuopio University Hospital, grid.410705.7
- (50) University of Eastern Finland, grid.9668.1
- (51) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
- (52) Cancer Research Initiatives Foundation, grid.427737.2
- (53) University Malaya Medical Centre, grid.413018.f
- (54) KU Leuven, grid.5596.f
- (55) Vesalius Research Center, Leuven, Belgium
- (56) University of Hawaii at Manoa, grid.410445.0
- (57) University of Warwick, grid.7372.1
- (58) Masaryk Memorial Cancer Institute, grid.419466.8
- (59) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
- (60) Cyprus Institute of Neurology and Genetics, grid.417705.0
- (61) University of Manchester, grid.5379.8
- (62) City Of Hope National Medical Center, grid.410425.6
- (63) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- (64) University of Groningen, grid.4830.f
- (65) IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
- (66) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland
- (67) University of Oulu, grid.10858.34
- (68) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
- (69) Shaukat Khanum Memorial Cancer Hospital and Research Center, grid.415662.2
- (70) National Cancer Institute of Thailand, grid.419173.9
- (71) King's College London, grid.13097.3c
- (72) Institute of Cancer Research, grid.18886.3f
- (73) China Medical University, grid.254145.3
- (74) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
- (75) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
- (76) University of Oxford, grid.4991.5
- (77) Pontificia Universidad Javeriana, grid.41312.35
- (78) National Taiwan University Hospital, grid.412094.a
- (79) Shanghai Municipal Center For Disease Control Prevention, grid.430328.e
- (80) University of Sydney, grid.1013.3
- (81) University of Otago, grid.29980.3a
- (82) Molecular Diagnostics Laboratory, Institute of Radioisotopes and Radiodiagnostic Products (IRRP), Athens, Greece
- (83) Ghent University Hospital, grid.410566.0
- (84) Ospedale San Martino, grid.410345.7
- (85) Moffitt Cancer Center, grid.468198.a
- (86) University of South Florida, grid.170693.a
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Description
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. Cancer Res; 77(11); 2789-99. ©2017 AACR.
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