Article
Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus
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- (1) United States Food and Drug Administration, grid.417587.8
- (2) National Cancer Institute, grid.48336.3a
- (3) University of Cambridge, grid.5335.0
- (4) University of Melbourne, grid.1008.9
- (5) Antoni van Leeuwenhoek Hospital, grid.430814.a
- (6) University of Manchester, grid.5379.8
- (7) University of Warwick, grid.7372.1
- (8) University of California, Los Angeles, grid.19006.3e
- (9) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- (10) Institute of Cancer Research, grid.18886.3f
- (11) King's College London, grid.13097.3c
- (12) University of Oxford, grid.4991.5
- (13) Heidelberg University, grid.7700.0
- (14) German Cancer Research Center, grid.7497.d
- (15) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
- (16) French Institute of Health and Medical Research, grid.7429.8
- (17) University of Paris-Sud, grid.5842.b
- (18) University of Copenhagen, grid.5254.6, KU
- (19) Herlev Hospital, grid.411900.d, Capital Region
- (20) Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain
- (21) Spanish National Cancer Research Centre, grid.7719.8
- (22) University of California, Irvine, grid.266093.8
- (23) City Of Hope National Medical Center, grid.410425.6
- (24) Technical University of Munich, grid.6936.a
- (25) University Hospital Cologne, grid.411097.a
- (26) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
- (27) University of Tübingen, grid.10392.39
- (28) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- (29) Kyushu University, grid.177174.3
- (30) Aichi Cancer Center, grid.410800.d
- (31) Hannover Medical School, grid.10423.34
- (32) Karolinska Institute, grid.4714.6
- (33) Kuopio University Hospital, grid.410705.7
- (34) University of Eastern Finland, grid.9668.1
- (35) QIMR Berghofer Medical Research Institute, grid.1049.c
- (36) University of Southern California, grid.42505.36
- (37) Universitair Ziekenhuis Leuven, grid.410569.f
- (38) KU Leuven, grid.5596.f
- (39) Vesalius Research Center, Leuven, Belgium
- (40) University Cancer Center Hamburg, grid.412315.0
- (41) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
- (42) European Institute of Oncology, grid.15667.33
- (43) Mayo Clinic, grid.66875.3a
- (44) Cancer Council Victoria, grid.3263.4
- (45) University of Hawaii at Manoa, grid.410445.0
- (46) McGill University, grid.14709.3b
- (47) Cancer Research Initiatives Foundation, grid.427737.2
- (48) University Malaya Medical Centre, grid.413018.f
- (49) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
- (50) Oslo University Hospital, grid.55325.34
- (51) University of Oslo, grid.5510.1
- (52) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America
- (53) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
- (54) University of Oulu, grid.10858.34
- (55) Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland
- (56) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
- (57) University of Toronto, grid.17063.33
- (58) Mount Sinai Hospital, grid.416166.2
- (59) Leiden University Medical Center, grid.10419.3d
- (60) Erasmus University Medical Center, grid.5645.2
- (61) Shanghai Center for Disease Control and Prevention, Shanghai, China
- (62) University of Sheffield, grid.11835.3e
- (63) International Epidemiology Institute, grid.419344.f
- (64) Seoul National University, grid.31501.36
- (65) National University Health System, grid.410759.e
- (66) National University of Singapore, grid.4280.e
- (67) Pontificia Universidad Javeriana, grid.41312.35
- (68) Pomeranian Medical University, grid.107950.a
- (69) National Cancer Institute of Thailand, grid.419173.9
- (70) International Agency For Research On Cancer, grid.17703.32
- (71) National Centre of Scientific Research Demokritos, grid.6083.d
- (72) China Medical University, grid.254145.3
- (73) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
- (74) Cancer Center and Department of Surgery, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- (75) Laval University, grid.23856.3a
- (76) University of Edinburgh, grid.4305.2
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The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.
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