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Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 4, 937-948, 20 March 2008

doi:10.1016/j.ajhg.2008.02.008

Article

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Antonis C. Antoniou^1, ,  , Amanda B. Spurdle², Olga M. Sinilnikova^3, 4, Sue Healey², Karen A. Pooley^1, 5, Rita K. Schmutzler⁶, Beatrix Versmold⁶, Christoph Engel⁷, Alfons Meindl⁸, Norbert Arnold⁹, Wera Hofmann¹⁰, Christian Sutter¹¹, Dieter Niederacher¹², Helmut Deissler¹³, Trinidad Caldes¹⁴, Kati Kämpjärvi¹⁵, Heli Nevanlinna¹⁵, Jacques Simard¹⁶, Jonathan Beesley², Xiaoqing Chen², the Kathleen Cuningham Consortium for Research into Familial Breast Cancer¹⁷, Susan L. Neuhausen¹⁸, Timothy R. Rebbeck¹⁹, Theresa Wagner²⁰, Henry T. Lynch²¹, Claudine Isaacs²², Jeffrey Weitzel²³, Patricia A. Ganz²⁴, Mary B. Daly²⁵, Gail Tomlinson²⁶, Olufunmilayo I. Olopade²⁷, Joanne L. Blum²⁸, Fergus J. Couch²⁹, Paolo Peterlongo³⁰, Siranoush Manoukian³¹, Monica Barile³², Paolo Radice³⁰, Csilla I. Szabo³³, Lutecia H. Mateus Pereira^34, 65, Mark H. Greene³⁵, Gad Rennert³⁶, Flavio Lejbkowicz³⁶, Ofra Barnett-Griness³⁶, Irene L. Andrulis^37, 38, 39, Hilmi Ozcelik^38, 39, OCGN³⁷, Anne-Marie Gerdes⁴⁰, Maria A. Caligo⁴¹, Yael Laitman⁴², Bella Kaufman⁴³, Roni Milgrom⁴², Eitan Friedman^42, 43, The Swedish BRCA1 and BRCA2 study collaborators⁴⁴, Susan M. Domchek⁴⁵, Katherine L. Nathanson⁴⁵, Ana Osorio⁴⁶, Gemma Llort⁴⁷, Roger L. Milne⁴⁸, Javier Benítez^46, 48, Ute Hamann⁴⁹, Frans B.L. Hogervorst⁵⁰, Peggy Manders⁵¹, Marjolijn J.L. Ligtenberg⁵², Ans M.W. van den Ouweland⁵³, The DNA-HEBON collaborators⁴⁴, Susan Peock¹, Margaret Cook¹, Radka Platte¹, D. Gareth Evans⁵⁴, Rosalind Eeles⁵⁵, Gabriella Pichert⁵⁶, Carol Chu⁵⁷, Diana Eccles⁵⁸, Rosemarie Davidson⁵⁹, Fiona Douglas⁶⁰, EMBRACE¹, Andrew K. Godwin²⁵, Laure Barjhoux^3, 4, Sylvie Mazoyer⁴, Hagay Sobol⁶¹, Violaine Bourdon⁶¹, François Eisinger⁶¹, Agnès Chompret^62, 66, Corinne Capoulade⁶³, Brigitte Bressac-de Paillerets⁶³, Gilbert M. Lenoir⁶³, Marion Gauthier-Villars⁶⁴, Claude Houdayer⁶⁴, Dominique Stoppa-Lyonnet⁶⁴, GEMO, Georgia Chenevix-Trench², Douglas F. Easton¹, on behalf of CIMBA

¹ Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK
² Queensland Institute of Medical Research, Brisbane, Australia
³ Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France
⁴ Laboratoire de Génétique Moléculaire, Signalisation et Cancer, UMR5201 CNRS, Université Lyon 1, Lyon, France
⁵ Cancer Research UK, Human Cancer Genetics Group, Department of Oncology, University of Cambridge, UK
⁶ Department of Obstetrics and Gynaecology, Division of Molecular Gynaeco-Oncology, University of Cologne, Germany
⁷ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany
⁸ Department of Obstetrics and Gynaecology, Technical University, Munich, Germany
⁹ Department of Obstetrics and Gynaecology, University of Schleswig-Holstein, Campus Kiel, Germany
¹⁰ Institute of Human Genetics, Charite-University Medical Centre, Berlin, Germany
¹¹ Institute of Human Genetics, University of Heidelberg, Germany
¹² Molecular Genetics Laboratory, Department of Obstetrics and Gynaecology, University of Düsseldorf, Germany
¹³ Department of Obstetrics and Gynaecology, University of Ulm, Germany
¹⁴ Hospital Clinico San Carlos, Madrid, Spain
¹⁵ Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland
¹⁶ Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Quebec and Laval University
¹⁷ Peter MacCallum Cancer Institute, Melbourne, Australia
¹⁸ Department of Epidemiology, University of California, Irvine, CA, USA
¹⁹ Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA
²⁰ University of Vienna, Vienna, Austria
²¹ Creighton University, Omaha, NE, USA
²² Fisher Center for Familial Cancer Research, Lombardi Cancer Center, Georgetown University, Washington, DC, USA
²³ City of Hope National Medical Center, Duarte, CA, USA
²⁴ UCLA Schools of Medicine & Public Health, and the UCLA Familial Cancer Registry of the Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA
²⁵ Fox Chase Cancer Center, Philadelphia, PA, USA
²⁶ University of Texas, Southwestern, Dallas, TX, USA
²⁷ University of Chicago, Chicago, IL, USA
²⁸ Baylor-Sammons Cancer Center, Dallas, Texas, USA
²⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
³⁰ Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori and IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
³¹ Medical Genetics Service, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
³² Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy
³³ Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
³⁴ Laboratory of Population Genetics, US National Cancer Institute, National Institutes of Health, Rockville, MD, USA
³⁵ Clinical Genetics Branch, National Cancer Institute, Rockville, MD, USA
³⁶ CHS National Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion, Haifa, Israel
³⁷ Ontario Cancer Genetics Network, Cancer Care Ontario, and Department of Molecular Genetics, University of Toronto, Ontario, Canada
³⁸ Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada
³⁹ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada
⁴⁰ Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Denmark
⁴¹ Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, Pisa, Italy
⁴² The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical center, Tel-Hashomer, Israel
⁴³ Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel
⁴⁴ See Acknowledgments
⁴⁵ Department of Medicine, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
⁴⁶ Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain
⁴⁷ Genetic Counselling Unit, Prevention and Cancer Control Service, Institut Català d'Oncologia, Barcelona, Spain
⁴⁸ Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain
⁴⁹ Deutsches Krebsforschungszentrum, Heidelberg, Germany
⁵⁰ Family Cancer Clinic, Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
⁵¹ Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
⁵² Department of Human Genetics and Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
⁵³ Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands
⁵⁴ Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, UK
⁵⁵ Translational Cancer Genetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, United Kingdom
⁵⁶ Clinical Genetics, Guy's Hospital, London, UK
⁵⁷ Yorkshire Regional Genetics Service, Leeds, UK
⁵⁸ Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
⁵⁹ Ferguson-Smith Centre for Clinical Genetics, Glasgow, UK
⁶⁰ Institute of Human Genetics, Centre for Life, Newcastle upon Tyne, UK
⁶¹ INSERM UMR599, Institut Paoli-Calmettes, Département d'Oncologie Génétique, Marseille 13275, France
⁶² Oncological Genetics, Department of Medicine, Institut Gustave Roussy, Villejuif, France
⁶³ CNRS FRE2939, Department of Genetics, Institut Gustave Roussy, Villejuif, France
⁶⁴ Institut Curie, Genetics Department, Université Paris-Descartes, France

Corresponding author

⁶⁵ Present address: University of Miami, Sylvester Cancer Center, Miami, FL, USA.

⁶⁶ Deceased.

Abstract

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20–1.45, p_trend = 1.7 × 10⁻⁸ and HR = 1.12, 95% CI: 1.02–1.24, p_trend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06–1.20, p_trend = 5 × 10⁻⁵ in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

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