Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
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 polymorphis...
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Published in | American journal of human genetics Vol. 82; no. 4; pp. 937 - 948 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Chicago, IL
Elsevier Inc
01.04.2008
University of Chicago Press Cell Press American Society of Human Genetics |
Subjects | |
Online Access | Get full text |
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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, ptrend = 1.7 × 10−8 and HR = 1.12, 95% CI: 1.02–1.24, ptrend = 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, ptrend = 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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AbstractList | 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 x 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 x 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. 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. 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, ptrend = 1.7 super(x) 10 super(-8) and HR = 1.12, 95% CI: 1.02-1.24, ptrend = 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, ptrend = 5 super(x) 10 super(-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. 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... = 1.7 x 10... and HR = 1.12, 95% CI: 1.02-1.24, P... = 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... = 5 x 10... 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. (ProQuest: ... denotes formulae/symbols omitted.) 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, ptrend = 1.7 × 10−8 and HR = 1.12, 95% CI: 1.02–1.24, ptrend = 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, ptrend = 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. |
Author | van den Ouweland, Ans M.W. Beesley, Jonathan Pooley, Karen A. Eeles, Rosalind Caligo, Maria A. Milne, Roger L. Neuhausen, Susan L. Lynch, Henry T. Manoukian, Siranoush Cook, Margaret Chenevix-Trench, Georgia Radice, Paolo Szabo, Csilla I. Gerdes, Anne-Marie Platte, Radka Chompret, Agnès Arnold, Norbert Blum, Joanne L. Easton, Douglas F. Pereira, Lutecia H. Mateus Niederacher, Dieter Ozcelik, Hilmi Hofmann, Wera Engel, Christoph Friedman, Eitan Daly, Mary B. Peock, Susan Greene, Mark H. Milgrom, Roni Couch, Fergus J. Gauthier-Villars, Marion Meindl, Alfons Olopade, Olufunmilayo I. Pichert, Gabriella Benítez, Javier Laitman, Yael Kaufman, Bella Antoniou, Antonis C. Barile, Monica Barnett-Griness, Ofra Deissler, Helmut Caldes, Trinidad Hogervorst, Frans B.L. Douglas, Fiona Domchek, Susan M. Sutter, Christian Osorio, Ana Chen, Xiaoqing Llort, Gemma Andrulis, Irene L. Ligtenberg, Marjolijn J.L. Capoulade, Corinne Manders, Peggy Eccles, Diana Sobol, Hagay Nevanlinna, Heli Peterlongo, Paolo Schmutzler, Rita K. Davidson, Rosemarie Godwin, Andrew K. Lej |
AuthorAffiliation | 23 City of Hope National Medical Center, Duarte, CA, USA 5 Cancer Research UK, Human Cancer Genetics Group, Department of Oncology, University of Cambridge, UK 61 INSERM UMR599, Institut Paoli-Calmettes, Département d'Oncologie Génétique, Marseille 13275, France 43 Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel 63 CNRS FRE2939, Department of Genetics, Institut Gustave Roussy, Villejuif, France 27 University of Chicago, Chicago, IL, USA 35 Clinical Genetics Branch, National Cancer Institute, Rockville, MD, USA 54 Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, UK 38 Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada 3 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France 9 Department of Obstetrics and Gynaecology, University of Schleswig-Holstein, Campus Kiel, Germany 31 Medical Genetics Service, Fondazione IRCCS Istituto Nazionale dei |
AuthorAffiliation_xml | – name: 16 Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Quebec and Laval University – name: 61 INSERM UMR599, Institut Paoli-Calmettes, Département d'Oncologie Génétique, Marseille 13275, France – name: 18 Department of Epidemiology, University of California, Irvine, CA, USA – name: 33 Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA – name: 50 Family Cancer Clinic, Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands – name: 49 Deutsches Krebsforschungszentrum, Heidelberg, Germany – name: 34 Laboratory of Population Genetics, US National Cancer Institute, National Institutes of Health, Rockville, MD, USA – name: 17 Peter MacCallum Cancer Institute, Melbourne, Australia – name: 23 City of Hope National Medical Center, Duarte, CA, USA – name: 3 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France – name: 44 See Acknowledgments – name: 54 Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, UK – name: 19 Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA – name: 13 Department of Obstetrics and Gynaecology, University of Ulm, Germany – name: 15 Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland – name: 42 The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical center, Tel-Hashomer, Israel – name: 41 Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, Pisa, Italy – name: 2 Queensland Institute of Medical Research, Brisbane, Australia – name: 26 University of Texas, Southwestern, Dallas, TX, USA – name: 31 Medical Genetics Service, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy – name: 46 Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain – name: 8 Department of Obstetrics and Gynaecology, Technical University, Munich, Germany – name: 7 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany – name: 6 Department of Obstetrics and Gynaecology, Division of Molecular Gynaeco-Oncology, University of Cologne, Germany – name: 48 Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain – name: 9 Department of Obstetrics and Gynaecology, University of Schleswig-Holstein, Campus Kiel, Germany – name: 12 Molecular Genetics Laboratory, Department of Obstetrics and Gynaecology, University of Düsseldorf, Germany – name: 55 Translational Cancer Genetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, United Kingdom – name: 40 Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Denmark – name: 1 Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK – name: 53 Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands – name: 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 – name: 5 Cancer Research UK, Human Cancer Genetics Group, Department of Oncology, University of Cambridge, UK – name: 14 Hospital Clinico San Carlos, Madrid, Spain – name: 39 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada – name: 60 Institute of Human Genetics, Centre for Life, Newcastle upon Tyne, UK – name: 28 Baylor-Sammons Cancer Center, Dallas, Texas, USA – name: 58 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK – name: 25 Fox Chase Cancer Center, Philadelphia, PA, USA – name: 45 Department of Medicine, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA – name: 64 Institut Curie, Genetics Department, Université Paris-Descartes, France – name: 57 Yorkshire Regional Genetics Service, Leeds, UK – name: 10 Institute of Human Genetics, Charite-University Medical Centre, Berlin, Germany – name: 11 Institute of Human Genetics, University of Heidelberg, Germany – name: 38 Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada – name: 27 University of Chicago, Chicago, IL, USA – name: 52 Department of Human Genetics and Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands – name: 20 University of Vienna, Vienna, Austria – name: 35 Clinical Genetics Branch, National Cancer Institute, Rockville, MD, USA – name: 59 Ferguson-Smith Centre for Clinical Genetics, Glasgow, UK – name: 63 CNRS FRE2939, Department of Genetics, Institut Gustave Roussy, Villejuif, France – name: 22 Fisher Center for Familial Cancer Research, Lombardi Cancer Center, Georgetown University, Washington, DC, USA – name: 21 Creighton University, Omaha, NE, USA – name: 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 – name: 62 Oncological Genetics, Department of Medicine, Institut Gustave Roussy, Villejuif, France – name: 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 – name: 56 Clinical Genetics, Guy's Hospital, London, UK – name: 51 Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands – name: 37 Ontario Cancer Genetics Network, Cancer Care Ontario, and Department of Molecular Genetics, University of Toronto, Ontario, Canada – name: 29 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA – name: 32 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy – name: 4 Laboratoire de Génétique Moléculaire, Signalisation et Cancer, UMR5201 CNRS, Université Lyon 1, Lyon, France – name: 43 Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel – name: 47 Genetic Counselling Unit, Prevention and Cancer Control Service, Institut Català d'Oncologia, Barcelona, Spain |
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ContentType | Journal Article |
Copyright | 2008 The American Society of Human Genetics 2008 INIST-CNRS Copyright University of Chicago, acting through its Press Apr 11, 2008 2008 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.. 2008 The American Society of Human Genetics |
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CorporateAuthor | EMBRACE GEMO study collaborators the Kathleen Cuningham Consortium for Research into Familial Breast Cancer The Swedish and The DNA-HEBON collaborators on behalf of CIMBA OCGN DNA-HEBON collaborators CIMBA Swedish BRCA1 and BRCA2 study collaborators Kathleen Cuningham Consortium for Research into Familial Breast Cancer |
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Keywords | Human Breast disease Pathogenesis Risk Breast cancer Malignant tumor Genetic determinism Genetic disease Mammary gland diseases Allele Association Genetic counseling Risk factor Predisposition Genetics Mutation Carrier Cancer Tumor suppressor gene |
Language | English |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Deceased. Present address: University of Miami, Sylvester Cancer Center, Miami, FL, USA. |
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Snippet | Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or... Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or... |
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SubjectTerms | Adult Aged Biological and medical sciences Breast cancer Breast Neoplasms - genetics Female Fundamental and applied biological sciences. Psychology General aspects. Genetic counseling Genes, BRCA1 Genes, BRCA2 Genetic Predisposition to Disease - genetics Genetics Genetics of eukaryotes. Biological and molecular evolution Genotype & phenotype Germ-Line Mutation Gynecology. Andrology. Obstetrics Humans Mammary gland diseases MAP Kinase Kinase Kinase 1 - genetics Medical genetics Medical sciences Middle Aged Molecular and cellular biology Mutation Polymorphism, Single Nucleotide Receptor, Fibroblast Growth Factor, Type 2 - genetics Risk Tumors |
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Title | Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers |
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