Article
Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation
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- (1) University of Cambridge, grid.5335.0
- (2) QIMR Berghofer Medical Research Institute, grid.1049.c
- (3) University of Queensland, grid.1003.2
- (4) Oslo University Hospital, grid.55325.34
- (5) Princess Margaret Cancer Centre, grid.415224.4
- (6) Dartmouth College, grid.254880.3
- (7) Antoni van Leeuwenhoek Hospital, grid.430814.a
- (8) Karolinska Institute, grid.4714.6
- (9) University of Copenhagen, grid.5254.6, KU
- (10) Department of Clinical Biochemistry, Herlev Hospital Copenhagen University Hospital, 2730, Herlev, Copenhagen, Denmark
- (11) Herlev Hospital, grid.411900.d, Capital Region
- (12) Flanders Institute for Biotechnology, grid.11486.3a
- (13) KU Leuven, grid.5596.f
- (14) Universitair Ziekenhuis Leuven, grid.410569.f
- (15) Mayo Clinic, grid.66875.3a
- (16) German Cancer Research Center, grid.7497.d
- (17) University Medical Center Hamburg-Eppendorf, grid.13648.38
- (18) London School of Hygiene & Tropical Medicine, grid.8991.9
- (19) Helsinki University Central Hospital, grid.15485.3d
- (20) Department of Clinical Genetics, University of Helsinki Helsinki University Central Hospital, FI-00029, Helsinki, HUS, Finland
- (21) Department of Oncology, University of Helsinki, Helsinki University Central Hospital, FI-00029, Helsinki, HUS, Finland
- (22) Genome Institute of Singapore, grid.418377.e
- (23) Seoul National University, grid.31501.36
- (24) Kyushu University, grid.177174.3
- (25) Aichi Cancer Center, grid.410800.d
- (26) French Institute of Health and Medical Research, grid.7429.8
- (27) University of Paris-Sud, grid.5842.b
- (28) Heidelberg University, grid.7700.0
- (29) National Center for Tumor Diseases, University of Heidelberg, 69120, Heidelberg, Germany
- (30) University of Southern California, grid.42505.36
- (31) Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010, Valencia, Spain
- (32) Spanish National Cancer Research Centre, grid.7719.8
- (33) Hospital Universitario La Paz, grid.81821.32
- (34) Hospital Monte Naranco, grid.414858.4
- (35) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 37203, Nashville, Tennessee, USA
- (36) Shanghai Center for Disease Control and Prevention, 200336, Shanghai, China
- (37) Shanghai Cancer Institute, grid.419087.3
- (38) University of Sheffield, grid.11835.3e
- (39) University of Toronto, grid.17063.33
- (40) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
- (41) Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, M5G 1X5, Toronto, Ontario, Canada
- (42) Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, M5G 1X5, Toronto, Ontario, Canada
- (43) King's College London, grid.13097.3c
- (44) Wellcome Centre for Human Genetics, grid.270683.8
- (45) University Hospital Galway, grid.412440.7
- (46) University of Hawaii at Manoa, grid.410445.0
- (47) University Malaya Medical Centre, grid.413018.f
- (48) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500, Subang JayaSelangor, Malaysia
- (49) National University of Singapore, grid.4280.e
- (50) Erasmus University Medical Center, grid.5645.2
- (51) University of Melbourne, grid.1008.9
- (52) College of Public Health, China Medical University, 40402, Taichung, Taiwan, China
- (53) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
- (54) Tri-Service General Hospital, grid.278244.f
- (55) Changhua Christian Hospital, grid.413814.b
- (56) University of Oslo, grid.5510.1
- (57) Cancer Council Victoria, grid.3263.4
- (58) The Alfred Hospital, grid.1623.6
- (59) University of Manchester, grid.5379.8
- (60) University of Warwick, grid.7372.1
- (61) Ministry of Public Health, grid.415836.d
- (62) National University Health System, grid.410759.e
- (63) University of California, Los Angeles, grid.19006.3e
- (64) Department of Gynecology and Obstetrics, University Breast Center Franconia, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054, Erlangen, Germany
- (65) Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany
- (66) Krebsregister Saarland, grid.482902.5
- (67) Institute of Cancer Research, grid.18886.3f
- (68) National Cancer Institute, grid.48336.3a
- (69) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
- (70) Laval University, grid.23856.3a
- (71) Royal Victoria Hospital, grid.416229.a
- (72) McGill University, grid.14709.3b
- (73) University of Montreal, grid.14848.31
- (74) Department of Clinical Chemistry and Biocenter Oulu, Laboratory of Cancer Genetics and Tumor Biology, NordLab Oulu/Oulu University Hospital University of Oulu, FI-90220, Oulu, Finland
- (75) Department of Oncology, Oulu University Hospital, University of Oulu, FI-90220, Oulu, Finland
- (76) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
- (77) University of Tübingen, grid.10392.39
- (78) Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789, Bochum, Germany
- (79) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, 53113, Bonn, Germany
- (80) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
- (81) FIRC Institute of Molecular Oncology, grid.7678.e
- (82) European Institute of Oncology, grid.15667.33
- (83) Cogentech Cancer Genetic Test Laboratory, 20133, Milan, Italy
- (84) Hannover Medical School, grid.10423.34
- (85) University of Eastern Finland, grid.9668.1
- (86) Kuopio University Hospital, grid.410705.7
- (87) Leiden University Medical Center, grid.10419.3d
- (88) Pomeranian Medical University, grid.107950.a
- (89) The Ohio State University, grid.261331.4
- (90) Roswell Park Cancer Institute, grid.240614.5
- (91) National Centre of Scientific Research Demokritos, grid.6083.d
- (92) National Cancer Institute of Thailand, grid.419173.9
- (93) International Agency For Research On Cancer, grid.17703.32
- (94) Pontificia Universidad Javeriana, grid.41312.35
- (95) University of California, Irvine, grid.266093.8
- (96) Department of Population Sciences, Beckman Research Institute of City of Hope, 92697, Duarte, California, USA
- (97) McGill University and Génome Québec Innovation Centre, grid.411640.6
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Description
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.