Article
Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium
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- (1) Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health
- (2) Cancer Council Victoria, grid.3263.4
- (3) Human Cancer Genetics Programme
- (4) Molecular Epidemiology Group
- (5) Department of Obstetrics and Gynecology
- (6) Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care
- (7) Hospital Monte Naranco, grid.414858.4
- (8) Hospital Universitario La Paz, grid.81821.32
- (9) Spanish National Cancer Research Centre, grid.7719.8
- (10) Institute of Cancer Research, grid.18886.3f
- (11) Division of Breast Cancer Research
- (12) Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research
- (13) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany
- (14) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
- (15) University of Tübingen, grid.10392.39
- (16) German Cancer Research Center, grid.7497.d
- (17) Department of Molecular Genetics
- (18) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- (19) University of Toronto, grid.17063.33
- (20) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
- (21) Kyushu University, grid.177174.3
- (22) Aichi Cancer Center, grid.410800.d
- (23) Mie University, grid.260026.0
- (24) Genome Institute of Singapore, grid.418377.e
- (25) Department of Medical Epidemiology and Biostatistics
- (26) Division of Clinical Epidemiology and Aging Research
- (27) Krebsregister Saarland, grid.482902.5
- (28) Flanders Institute for Biotechnology, grid.11486.3a
- (29) Universitair Ziekenhuis Leuven, grid.410569.f
- (30) Pomeranian Medical University, grid.107950.a
- (31) Saw Swee Hock School of Public Health, Department of Surgery, Yong Loo Lin School of Medicine
- (32) National University of Singapore, grid.4280.e
- (33) National University Health System, grid.410759.e
- (34) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
- (35) Heidelberg University, grid.7700.0
- (36) Department of Molecular Medicine and Surgery
- (37) Karolinska Institute, grid.4714.6
- (38) National Cancer Institute, grid.48336.3a
- (39) Breakthrough Breast Cancer Research Centre
- (40) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
- (41) Copenhagen General Population Study, Herlev Hospital
- (42) Department of Clinical Biochemistry, Herlev Hospital
- (43) University of Copenhagen, grid.5254.6, KU
- (44) Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- (45) Department of Medical Oncology
- (46) Erasmus University Medical Center, grid.5645.2
- (47) London School of Hygiene & Tropical Medicine, grid.8991.9
- (48) Vanderbilt University Medical Center, grid.412807.8
- (49) Institute for Medical Biometrics and Epidemiology
- (50) University Medical Center Hamburg-Eppendorf, grid.13648.38
- (51) University of Oulu, grid.10858.34
- (52) Department of Oncology
- (53) Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland
- (54) CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology
- (55) University of Sheffield, grid.11835.3e
- (56) Antoni van Leeuwenhoek Hospital, grid.430814.a
- (57) Seoul National University, grid.31501.36
- (58) Department of Preventive Medicine
- (59) Laval University, grid.23856.3a
- (60) McGill University, grid.14709.3b
- (61) Royal Victoria Hospital, grid.416229.a
- (62) University of Montreal, grid.14848.31
- (63) University of California, Los Angeles, grid.19006.3e
- (64) University Breast Center Franconia, Department of Gynecology and Obstetrics
- (65) Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- (66) Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine
- (67) FIRC Institute of Molecular Oncology, grid.7678.e
- (68) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
- (69) European Institute of Oncology, grid.15667.33
- (70) King's College London, grid.13097.3c
- (71) University of Oxford, grid.4991.5
- (72) Wellcome Centre for Human Genetics, grid.270683.8
- (73) National University of Ireland, Galway, grid.6142.1
- (74) University of Melbourne, grid.1008.9
- (75) University Malaya Medical Centre, grid.413018.f
- (76) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
- (77) China Medical University, grid.254145.3
- (78) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
- (79) Tri-Service General Hospital, grid.278244.f
- (80) Cancer Center
- (81) Kaohsiung Medical University Chung-Ho Memorial Hospital, grid.412027.2
- (82) University of Paris-Sud, grid.5842.b
- (83) French Institute of Health and Medical Research, grid.7429.8
- (84) Centre de Ressources Biologiques EPIGENETEC, Paris, France
- (85) Vanderbilt University, grid.152326.1
- (86) Helsinki University Central Hospital, grid.15485.3d
- (87) Department of Clinical Genetics
- (88) University of Southern California, grid.42505.36
- (89) Hannover Medical School, grid.10423.34
- (90) Department of Obstetrics and Gynaecology
- (91) University of Manchester, grid.5379.8
- (92) University of Warwick, grid.7372.1
- (93) Ministry of Public Health, grid.415836.d
- (94) Biocenter Kuopio
- (95) Department of Clinical Pathology
- (96) School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine
- (97) Kuopio University Hospital, grid.410705.7
- (98) University of Eastern Finland, grid.9668.1
- (99) Shanghai Center for Disease Control and Prevention, Shanghai, China
- (100) Shanghai Cancer Institute, grid.419087.3
- (101) Department of Laboratory Medicine and Pathology
- (102) Department of Health Sciences Research
- (103) The Ohio State University, grid.261331.4
- (104) National Centre of Scientific Research Demokritos, grid.6083.d
- (105) National Cancer Institute of Thailand, grid.419173.9
- (106) International Agency For Research On Cancer, grid.17703.32
- (107) University of Hawaii at Manoa, grid.410445.0
- (108) Department of Human Genetics, and
- (109) Leiden University Medical Center, grid.10419.3d
- (110) University of Cambridge, grid.5335.0
- (111) QIMR Berghofer Medical Research Institute, grid.1049.c
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Description
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
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