Human Molecular Genetics Advance Access published online on January 6, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddn429
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Association of ESR1 gene tagging SNPs with breast cancer risk
1 Depts. of Oncology & Genetic Epidemiology, Strangeways Research Lab., Worts Causeway Cambridge CB1 8RN. UK 2 MRC Centre for Nutritional Epidemiology, Strangeways Research Lab., Worts Causeway, Cambridge CB1 8RN, UK 3 Dept. of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089 and Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii 96813, USA 4 Divisions of Experimental Therapy & Epidemiology, Netherlands Cancer Inst., Amsterdam, The Netherlands 5 Cancer Epidemiology Centre, The Cancer Council Victoria & Genetic Epidemiology Lab. Dept of Pathology, University of Melbourne, Melbourne, Australia 6 University Breast Center Franken, University Hospital Erlangen, Germany & University of California at Los Angeles, Dept. of Hematology and Oncology, David Geffen School of Medicine, USA 7 Cancer Research-UK Epidemiology & Genetics Unit, LHSTM, London WC1E 7HT & Breakthrough Breast Cancer Research Centre, ICR, London, SW3 6JB, UK 8 Dept. of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, DK-2730 Herlev, Denmark 9 Human Cancer Genetics Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), & Centro Nacional Genotipación (CEGEN) Madrid, Spain 10 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, & Dept. of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany 11 Division of Molecular Gynaeco-Oncology, Dept. of Gynaecology and Obstetrics, Clinical Center University of Cologne, & Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center, DKFZ, Heidelberg, Germany 12 Clinics of Obstetrics and Gynaecology & Clinics of Radiation Oncology, Hannover Medical School, 30625 Hannover, Germany 13 Dept. of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland 14 Dept. of Molecular Medicine & Surgery, Karolinska Inst., S17176 & Dept of Oncology, Karolinska University Hospital at Södersjukhuset, S 118 83 Stockholm, Sweden 15 Inst. of Clinical Medicine, Pathology and Forensic Medicine, University of Kuopio & Dept of Pathology, University Hospital of Kuopio, Kuopio FIN-70211, Finland 16 QIMR, Royal Brisbane Hospital, Herston, QLD 4029 Brisbane & Peter MacCallum Cancer Centre, East Melbourne, Australia 17 Division of Cancer Epidemiology, DFKZ, Heidelberg & Inst. for Medical Biometrics & Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany 18 Depts. of Laboratory Medicine & Pathology and Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55902, USA 19 Center for Molecular Environmental, Genetic, and Analytical Epidemiology, University of Melbourne, Australia & Genetic Epidemiology Lab,, Dept. of Pathology, University of Melbourne, Australia 20 Department of Genetics, Inst. for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, & Faculty of Medicine, University of Oslo, Oslo, Norway 21 Dept of Epidemiology, Harvard School of Public Health & Channing Lab. Dept. of Medicine, Brigham & Women's Hospital, Boston USA 22 Dept. of Human Genetics, Dept of Pathology, Leiden University Medical Center, & M.P.G. Vreeswijk Dept. of Human Genetics, LUMC, Leiden, The Netherlands 23 Dept. of Cancer Epidemiology and Prevention. The M. Sklodowska-Curie Memorial Cancer Center and Inst. of Oncology, Poland & Division of Cancer Epidemiology and Genetics, National Cancer Inst., Rockville, Maryland 20852-7234, USA 24 Human Genetics, Genome Inst. of Singapore, Singapore & Dept of Medical Epidemiology & Biostatistics, Karolinska Inst, Sweden 25 Seoul National University College of Medicine, Seoul, Korea 26 Inst. of Biomedical Sciences, Academia Sinica, Taipei, 115 & Dept. of Surgery, Tri-Service General Hospital, Taipei, 114. aiwan 27 Dept of Epidemiology, School of Medicine, University of California-Irvine, Irvine. CA. USA 28 Radiation Epidemiology Branch, Division of Cancer Epidemiology & Genetics, NCI, NIH, DHHS, Bethesda, & Population Genomics, National Human Genome Research Institute, Rockville, MD, USA
* Corresponding author - AMD e-mail alisond{at}srl.cam.ac.uk Phone: +44 (0)1223 740683, Fax: +44(0)1223 740147
We have conducted a three-stage, comprehensive SNP-tagging association study of ESR1 gene variants (SNPs) in more than 55 000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an Odds Ratio (OR) = 1.05 [95% Confidence Intervals (CI) 1.02-1.09] relative to t-allele homozygotes, P= 0.004. There is significant heterogeneity between studies, P= 0.002. The increased risk appears largely confined to estrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, indicating that it may be functional.