1 Klinik Diagnostik, The Faculty of Medicine, Aalborg University, VBN2 Klinisk Biokemi, The Faculty of Medicine, Aalborg University, VBN3 Aalborg University Hospital, The Faculty of Medicine, Aalborg University, VBN4 The Faculty of Medicine, Aalborg University, VBN5 none, IFOM, Fondazione Istituto FIRC di Oncologia Molecolare email@example.com Division of Cancer Epidemiology, German Cancer Research Center (DKFZ).7 Department of Cancer Prevention and Control, Roswell Park Cancer Institute.8 Center for Molecular Medicine Cologne, University of Cologne.9 Centre Hospitalier Universitaire de Québec Research Center and Laval University.10 Royal Marsden NHS Foundation Trust11 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge.12 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ).13 Genomic Epidemiology, German Cancer Research Center (DKFZ).14 Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ).15 Department of Epidemiology, The Netherlands Cancer Institute.16 Molecular Cancer Epidemiology Laboratory, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute.17 Department of Pathology, University of Otago.18 Department of Biomedical Sciences and Medicine, University of Algarve.19 Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS.20 Department of Genetics and Pathology, Pomeranian Medical University.21 Department of Genetics and Pathologyy, Pomeranian Medical University.22 Department of Clinical Genetics, Maastricht University Medical Center.23 Center for Clinical Cancer Genetic, Department of Medicine, The University of Chicago.24 Department of Medicine and Institute for Human Genetics, University of California, San Francisco.25 Department of Medicine, Abramson Cancer Center, University of Pennsylvania.26 Department of Epidemiology and Biostatistics, University of Pennsylvania.27 Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center.28 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center.29 Department of Pediatrics and Medicine, Columbia University.30 Department of Genetics and Genomics, Case Western Reserve Medical School.31 Genetic Epidemiology Laboratory, The University of Melbourne.32 Department of Dermatology, University of Utah School of Medicine.33 Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah School of Medicine.34 Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics.35 University of Pretoria36 Beckman Research Institute, Department of Population Sciences, City of Hope.37 Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.38 Department of Clinical Genetics, Copenhagen University Hospital.39 Department of Oncology, Copenhagen University Hospital.40 Human Genetics Group, Spanish National Cancer Centre (CNIO).41 Hospital de Cruces42 care of City of Hope Clinical Cancer Genetics Community Research Network, Saint Alphonsus Regional Medical Center.43 Clinical Cancer Genetics, City of Hope.44 Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT).45 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia.46 IFOM, Fondazione Istituto FIRC di Oncologia Molecolare.47 Experimental Oncology 1, CRO Aviano National Cancer Institute.48 Department of Molecular Medicine, Sapienza University.49 Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence.50 Unit of Genetic Counseling, Medical Oncology Department, Istituto Nazionale Tumori Regina Elena.51 Ospedale di Circolo52 Molecular Diagnostics Laboratory IRRP, National Centre for Scientific Research.53 Medical Oncology, Dana-Farber Cancer Institute.54 Clinical Genetics Department, St Michael's Hospital.55 Royal Devon & Exeter Hospital.56 Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust.57 Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust.58 Southampton University Hospitals NHS Trust59 Kennedy-Galton Centre, North West Thames Regional Genetics Service.60 Sheffield Children's Hospital61 Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital.62 Yorkshire Regional Centre for Cancer Studies.63 University Hospitals of Leicester NHS Trust64 Oxford Regional Genetics Service.65 Guy's and St Thomas' NHS Foundation Trust66 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust.67 Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St. James's Hospital.68 University Hospital of Wales69 South East of Scotland Regional Genetics Service.70 Centre for Cancer Research and Cell Biology, Queens University of Belfast, Belfast HSC Trust.71 Department of Public Health and Primary Care, University of Cambridge.72 Yorkhill Hospitals, Ferguson-Smith Centre for Clinical Genetics.73 Medical Genetics Unit, St George's, University of London.74 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust.75 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center.76 Center for Medical Genetics, Ghent University.77 Department of Gynaecology and Obstetrics, Technical University Munich.78 Institute of Human Genetics, University Wurzburg.79 Institut of Humangenetics, University of Heidelberg.80 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig.81 Obstetrics & Gynecology, Heinrich Heine University Düsseldorf.82 Institute of Cell and Molecular Pathology, Hannover Medical School.83 Institute of Human Genetics, University Hospital of Schleswig-Holstein/University Kiel.84 Department of Obstetrics and Gynecology, Technische Universität Dresden.85 Center for Molecular Medicine Cologne (CMMC), University of Cologne.86 Department of Obstetrics and Gynecology, Ludwig Maximilians University Munich.87 Clinic of Obstetrics and Gynecology, University Hospital of Schleswig-Holstein/University Kiel.88 Institute of Human Genetics, Charite Campus Virchow-Klinikum Humbold Universität.89 Department of Gynaecology and Obstetrics, University of Ulm.90 Service de Génétique, Institut de Cancerologie Gustave Roussy.91 Department of Tumour Biology, Institut Curie, Université Paris-Descartes.92 Centre René Gauducheau.93 Department of Tumor Biology, Institut Curie, Université Paris-Descartes.94 Service de Génétique Oncologique, Institut Curie.95 Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université Lyon 1.96 Unité d'Oncogénétique, CHU Arnaud de Villeneuve Montpellier.97 Department of Medical Oncology, Centre Hospitalier Universitaire Dupuytren.98 Centre Leon Berard99 Consultation de Génétique, Département de Médecine, Institut de Cancérologie Gustave Roussy.100 Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute.101 Australia New Zealand Gynaecological Oncology Group (ANZGOG).102 Division of Gynecologic Oncology, NorthShore University HealthSystem.103 Department of Obstetrics and Gynecology, Ohio State University.104 Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC.105 Department of Oncology, Hospital Clinico San Carlos, IdISSC.106 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital.107 Department of Clinical Genetics, Helsinki University Central Hospital.108 Department of Clinical Genetics, Academic Medical Center.109 Department of Clinical Genetics, VU University Medical Centre.110 Department of Genetics, University Medical Center Groningen, University of Groningen.111 Department of Human Genetics, Leiden University Medical Center (LUMC).112 Department of Human Genetics, Radboud University Medical Center.113 Department of Medical Genetics, University Medical Centre Utrecht.114 Erasmus University Medical Center Cancer Institute, Department of Obstetrics and Gynaecology, Erasmus University Medical Center.115 Department of Clinical Genetics, Erasmus University Medical Center.116 Department of Molecular Oncology, National Institute of Oncology.117 Oncogenetics, Vall d'Hebron Institute of Oncology (VHIO).118 Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology.119 Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology.120 Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI-Catalan Institute of Oncology.121 Landspitali University Hospital122 Centre des maladies du sein Deschênes-Fabia, Centre de Recherche FRSQ du Centre Hospitalier Affilié Universitaire de Québec.123 Department of Genetics, Portuguese Oncology Institute-Porto.124 Department of Health Sciences Research, Mayo Clinic.125 Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic.126 Department of Health Science Research, Mayo Clinic.127 Department of Laboratory Medicine and Pathology, Mayo Clinic.128 Building 50, Room 5312, National Human Genome Research Institute, National Institutes of Health.129 Clinical Genetics Research Laboratory, Memorial Sloan-Kettering Cancer Center.130 Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center.131 Diagnostic Molecular Genetics Laboratory, Department of Pathology, Memorial Sloan-Kettering Cancer Center.132 Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna.133 OB/GYN, Medical University of Vienna.134 Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute.135 Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, National Institutes of Health.136 Clalit National Cancer Control Center Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology.137 University of Toronto138 Ontario Cancer Genetics Network: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.139 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.140 Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University.141 Department of Clinical Genetics, Vejle Hospital.142 Dept. of Clinical Genetics, Odense University Hospital.143 Department of Clinical Genetics, Aarhus University Hospital.144 Sheba Medical Center.145 Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.146 Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.147 Department of Immunology, Genetics and Pathology, Uppsala University.148 Department of Clinical and Experimental Medicine, Linköping University.149 Department of Oncology, Clinical Science, Lund University, Lund, Sweden.150 Centre for Cancer Epidemiology, Department of Public Health, University of Cambridge.151 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute.152 Department of Oncology, University of Cambridge.153 Cancer Division, QIMR Berghofer Medical Research Institute.154 Oncogenetics Unit, Sheba Medical Center.155 Royal Marsden NHS Foundation Trust156 University of Pretoria157 Hospital de Cruces158 Ospedale di Circolo159 Southampton University Hospitals NHS Trust160 Sheffield Children's Hospital161 University Hospitals of Leicester NHS Trust162 Guy's and St Thomas' NHS Foundation Trust163 University Hospital of Wales164 Centre Leon Berard165 Landspitali University Hospital166 University of Toronto
BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
Cancer Epidemiology, Biomarkers and Prevention, 2015, Vol 24, Issue 1, p. 308-316
Adult; Breast Neoplasms; Cohort Studies; Female; Genes, BRCA1; Genes, BRCA2; Humans; Mutation; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Retrospective Studies; Young Adult; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.