Human Molecular Genetics Advance Access originally published online on August 5, 2009
Human Molecular Genetics 2009 18(22):4442-4456; doi:10.1093/hmg/ddp372
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Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers
1 Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, UK, 2 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, UMR5201 CNRS, Université de Lyon, Lyon, France, 3 Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia, 4 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland, 5 Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec, Canada, 6 Peter MacCallum Cancer Institute, Melbourne VIC 3002, Australia, 7 Department of Epidemiology, University of California Irvine, Irvine, CA, USA, 8 Mayo Clinic, Rochester, MN, USA, 9 Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, 10 Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy, 11 Istituto Europeo di Oncologia, Milan, Italy, 12 Centro di Riferimento Oncologico, IRCCS, Aviano, PN, Italy, 13 Cogentech, Consortium for Genomic Technologies, Milan, Italy, 14 Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA, 15 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic, 16 Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic, 17 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium, 18 Clinical Genetics Branch, US National Cancer Institute, Rockville, MD, USA, 19 CHS National Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion, Haifa, Israel, 20 Ontario Cancer Genetics Network, Cancer Care Ontario, Ontario, Canada, 21 Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Ontario, Canada, 22 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada, 23 Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark, 24 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark, 25 Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, Pisa, Italy, 26 The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel Hashomer, Israel, 27 The Oncology Institute Chaim Sheba Medical Center, Tel Hashomer, Israel, 28 The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel, 29 Genetics Institute Rambam Medical Center, Haifa, Israel, 30 Department Oncology, Lund University, Sweden, 31 Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden, 32 Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden, 33 Department of Oncology, Sahlgrenska University, Gothenburg, Sweden, 34 University of Pennsylvania, Philadelphia, PA, USA, 35 Group of Human Genetics, Human Cancer Genetics Programme, Spanish National Cancer Centre (CNIO) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERERER), Instituto de Salud Carlos III, Madrid, Spain, 36 Cancer Genetics Counseling Program, Catalan Institute of Oncology (ICO), Barcelona, Spain, 37 Genetics Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 38 Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580 69120, Heidelberg, Germany, 39 Family Cancer Clinic, Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands, 40 Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands, 41 Department of Clinical Genetics, Rotterdam Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands, 42 Department of Genetic Epidemiology and 43 Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands, 44 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands, 45 Department of Clinical Molecular Genetics, Utrecht University Medical Center, The Netherlands, 46 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands, 47 Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands, 48 Department of Clinical Genetics, University Medical Center, Maastricht, The Netherlands, 49 HEereditary Breast and Ovarian cancer group Netherlands (HEBON), 50 Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK, 51 Translational Cancer Genetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK, 52 Clinical Genetics, Guy's Hospital, London, UK, 53 Ferguson-Smith Centre for Clinical Genetics, Glasgow, UK, 54 Yorkshire Regional Genetics Service, Leeds, UK, 55 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK, 56 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK, 57 Department of Cancer Genetics, St Georges Hospital, University of London, London, UK, 58 Fox Chase Cancer Center, Philadelphia, PA, USA, 59 INSERM U509, Service de Génétique Oncologique, Institut Curie, and Université Paris-Descartes, Paris, France, 60 Département de Génétique, Institut Curie, Paris, France, 61 Genetics Department, Institut de Cancérologie Gustave Roussy, Villejuif, France, 62 INSERM U946, Institut de Cancérologie Gustave Roussy, Villejuif, France, 63 Consultation de Génétique, Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif, France, 64 CNRS FRE2939, Institut de Cancérologie Gustave Roussy, Villejuif, France, 65 Laboratoire de Génétique Constitutionnelle, Institut Bergonié, Bordeaux, France, 66 INSERM U916, Institut Bergonié, Bordeaux, France, 67 Laboratoire de Génétique Chromosomique, Hôtel Dieu Centre Hospitalier, Chambéry, France, 68 Service de Génétique Clinique Chromosomique et Moléculaire, CHU de St Etienne, St Etienne, France, 69 Department of Dermatology, University of Utah, Utah, USA, 70 Dana-Farber Cancer Institute, Boston, MA, USA, 71 Northern California Cancer Center, Fremont and Stanford University School of Medicine, Stanford, CA, USA, 72 Huntsman Cancer Institute, University of Utah Health Sciences Centre, Salt Lake City, UT, USA, 73 The University of Melbourne, Melbourne, Australia, 74 Columbia University, New York, NY, USA, 75 Division of Special Gynecology, Department of OB/GYN, Medical University of Vienna, Vienna, Austria, 76 Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, 77 Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland, 78 Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 79 GOG Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, 80 NorthShore University Health System, Evanston Northwestern Healthcare, Evanston IL 60201, USA, 81 New England Medical Center, Tufts University, Boston, MA 02111, USA, 82 University of North Carolina, Chapel Hill, NC 27599, USA, 83 St Elizabeth Medical Center, Edgewood, KY 41017, USA, 84 Yale University School of Medicine, New Haven, CT 06510, USA, 85 New York University School of Medicine, New York, NY 10016, USA, 86 Department of Internal Medicine and 87 Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA, 88 Istituto Oncologico Veneto, IRCCS, Immunology and Molecular Oncology Unit, Padua, Italy, 89 N.N. Petrov Institute of Oncology, St Petersburg, Russia, 90 Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy, 91 Department of Obstetrics and Gynaecology, Division of Molecular Gynaeco-Oncology, University of Cologne, Cologne, Germany, 92 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany, 93 Department of Obstetrics and Gynaecology, Technical University Munich, Munich, Germany, 94 Department of Obstetrics and Gynecology, Ludwig-Maximilian University Munich, Munich, Germany, 95 Department of Obstetrics and Gynaecology, University of Schleswig-Holstein, Campus Kiel, Germany, 96 Molecular Genetics Laboratory, Department of Obstetrics and Gynaecology, University of Duesseldorf, Duesseldorf, Germany, 97 Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany, 98 Institute of Human Genetics, University of Regensburg, Regensburg, Germany, 99 Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany, 100 Institute of Human Genetics, University of Würzburg, Würzburg, Germany, 101 Institute of Cellular and Molecular Pathology, Medical University, Hannover, Germany and 102 Hospital Clinico San Carlos 28040, Madrid, Spain
* To whom correspondence should be addressed at: CR-UK Genetic Epidemiology, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK. Tel: +44 1223740163; fax: +44 122740159; Email: antonis{at}srl.cam.ac.uk
Received May 26, 2009; Accepted August 3, 2009
Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07–1.25, P-trend = 2.8 x 10–4]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04–1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04–1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98–1.14) was consistent with odds ratio estimates derived from population-based case–control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.