Human Molecular Genetics Advance Access originally published online on January 6, 2009
Human Molecular Genetics 2009 18(6):1131-1139; doi:10.1093/hmg/ddn429
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Association of ESR1 gene tagging SNPs with breast cancer risk
1 Department of Oncology 2 Department of Public Health, University of Cambridge, Cambridge, UK 3 Li Ka Shing Centre, CR-UK Cambridge Research Institute, London WC2A 3PX, UK 4 MRC Centre for Nutritional Epidemiology, Cambridge, UK 5 Department of Preventive Medicine, University of Southern California, Alhambra, CA 91803, USA 6 Cancer Research Center, University of Hawaii, Honolulu, HI 96822, USA 7 Divisions of Experimental Therapy and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands 8 Center for Molecular Environmental, Genetic and Analytical Epidemiology, University of Melbourne, Melbourne, Australia 9 Genetic Epidemiology Lab, Department of Pathology, University of Melbourne, Melbourne, Australia 10 University Breast Center Franken, University Hospital Erlangen, Erlangen, Germany 11 Department of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA 12 CR-UK Epidemiology and Genetics Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK 13 CR-UK Epidemiology and Genetics Group, Institute of Cancer Research, Sutton, UK 14 Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK 15 Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark 16 Human Cancer Genetics Programme, CNIO, Madrid, Spain 17 CEGEN, Madrid, Spain 18 Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany 19 Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Bonn, Germany 20 Department of Gynaecology and Obstetrics, University of Cologne, Cologne, Germany 21 Group Molecular Epidemiology, DKFZ, Heidelberg, Germany 22 Clinic of Obstetrics and Gynaecology 23 Clinic of Radiation Oncology, Hannover Medical School, Germany 24 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Finland 25 Department of Molecular Medicine and Surgery 26 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden 27 Department of Oncology, Karolinska University Hospital, Stockholm, Sweden 28 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Kuopio, Kuopio, Finland 29 Department of Pathology, University Hospital of Kuopio, Kuopio, Finland 30 QIMR, Royal Brisbane Hospital, Herston, QLD, Australia 31 Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia 32 Division of Cancer Epidemiology, DFKZ Heidelberg, Heidelberg, Germany 33 Institute for Medical Biometrics & Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany 34 Department of Laboratory Medicine and Pathology 35 Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA 36 Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, VIC 3053, Australia 37 Department of Genetics, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway 38 Faculty of Medicine, University of Oslo, Oslo, Norway 39 Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA 40 Channing Lab, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA 41 Department of Human Genetics 42 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands 43 Department of Cancer Epidemiology and Prevention, The M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 44 Division of Cancer Epidemiology and Genetics, NCI, MD, USA 45 Human Genetics, Genome Institute of Singapore, Singapore 46 Seoul National University College of Medicine, Seoul, South Korea 47 Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Republic of China 48 Deparment of Surgery, Tri-Service General Hospital, Taipei, Taiwan, Republic of China 49 Deparment of Epidemiology, School of Medicine, University of California at Irvine, Irvine, CA 92697, USA 50 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Bethesda, MD 20892-7242, USA 51 Population Genomics, NHGRI, Bethesda, MD 20892-2154, USA
* To whom correspondence should be addressed at: Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK. Tel: +44 1223740683; Fax: +44 1223740147; Email: alisond{at}srl.cam.ac.uk
We have conducted a three-stage, comprehensive single nucleotide polymorphism (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) of 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 oestrogen 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, and it may subtly alter the ratio of two mRNA splice forms.