Fulltext

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

Rebbeck TR 1 , Mitra N 2 , Wan F 2 , Sinilnikova OM 3 , Healey S 4 , McGuffog L 5 Show all authors , Mazoyer S 3 , Chenevix-Trench G 4 , Easton DF 5 , Antoniou AC 5 , Nathanson KL 6 , CIMBA Consortium , Laitman Y 7 , Kushnir A 8 , Paluch-Shimon S 7 , Berger R 9 , Zidan J 10 , Friedman E 7 , Ehrencrona H 11 , Stenmark-Askmalm M 12 , Einbeigi Z 13 , Loman N 14 , Harbst K 14 , Rantala J 15 , Melin B 16 , Huo D 17 , Olopade OI 17 , Seldon J 18 , Ganz PA 18 , Nussbaum RL 19 , Chan SB 20 , Odunsi K 21 , Gayther SA 22 , Domchek SM 6 , Arun BK 23 , Lu KH 23 , Mitchell G 24 , Karlan BY 25 , Walsh C 25 , Lester J 25 , Godwin AK 26 , Pathak H 26 , Ross E 27 , Daly MB 28 , Whittemore AS 20 , John EM 29 , Miron A 30 , Terry MB 31 , Chung WK 32 , Goldgar DE 33 , Buys SS 34 , Janavicius R 35 , Tihomirova L 36 , Tung N 37 , Dorfling CM 38 , van Rensburg EJ 38 , Steele L 39 , Neuhausen SL 39 , Ding YC 39 , Ejlertsen B 40 , Gerdes AM 40 , Hansen Tv 41 , Ramón y Cajal T 42 , Osorio A 43 , Benitez J 44 , Godino J 45 , Tejada MI 46 , Duran M 47 , Weitzel JN 48 , Bobolis KA 48 , Sand SR 48 , Fontaine A 48 , Savarese A 49 , Pasini B 50 , Peissel B 51 , Bonanni B 52 , Zaffaroni D 51 , Vignolo-Lutati F 53 , Scuvera G 51 , Giannini G 54 , Bernard L 55 , Genuardi M 56 , Radice P 57 , Dolcetti R 58 , Manoukian S 51 , Pensotti V 59 , Gismondi V 60 , Yannoukakos D 61 , Fostira F 61 , Garber J 30 , Torres D 62 , Rashid MU 63 , Hamann U 64 , Peock S 5 , Frost D 5 , Platte R 5 , Evans DG 65 , Eeles R 66 , Davidson R 67 , Eccles D 68 , Cole T 69 , Cook J 70 , Brewer C 71 , Hodgson S 72 , Morrison PJ 73 , Walker L 74 , Porteous ME 75 , Kennedy MJ 76 , Izatt L 77 , Adlard J 78 , Donaldson A 79 , Ellis S 5 , Sharma P 80 , Schmutzler RK 81 , Wappenschmidt B 81 , Becker A 81 , Rhiem K 81 , Hahnen E 81 , Engel C 82 , Meindl A 83 , Engert S 83 , Ditsch N 83 , Arnold N 84 , Plendl HJ 85 , Mundhenke C 84 , Niederacher D 86 , Fleisch M 86 , Sutter C 87 , Bartram CR 87 , Dikow N 87 , Wang-Gohrke S 88 , Gadzicki D 89 , Steinemann D 89 , Kast K 90 , Beer M 91 , Varon-Mateeva R 92 , Gehrig A 93 , Weber BH 94 , Stoppa-Lyonnet D 95 , Sinilnikova OM 96 , Mazoyer S 97 , Houdayer C 98 , Belotti M 99 , Gauthier-Villars M 99 , Damiola F 97 , Boutry-Kryza N 100 , Lasset C 101 , Sobol H 102 , Peyrat JP 103 , Muller D 104 , Fricker JP 104 , Collonge-Rame MA 105 , Mortemousque I 106 , Nogues C 107 , Rouleau E 108 , Isaacs C 109 , De Paepe A 110 , Poppe B 110 , Claes K 110 , De Leeneer K 110 , Piedmonte M 111 , Rodriguez G 112 , Wakely K 113 , Boggess J 114 , Blank SV 115 , Basil J 116 , Azodi M 117 , Phillips KA 24 , Caldes T 118 , de la Hoya M 118 , Romero A 118 , Nevanlinna H 119 , Aittomäki K 120 , van der Hout AH 121 , Hogervorst FB 122 , Verhoef S 122 , Collée JM 123 , Seynaeve C 124 , Oosterwijk JC 121 , Gille JJ 125 , Wijnen JT 126 , Gómez Garcia EB 127 , Kets CM 128 , Ausems MG 129 , Aalfs CM 130 , Devilee P 131 , Mensenkamp AR 128 , Kwong A 132 , Olah E 133 , Papp J 133 , Diez O 134 , Lazaro C 135 , Darder E 136 , Blanco I 137 , Salinas M 137 , Jakubowska A 138 , Lubinski J 138 , Gronwald J 138 , Jaworska-Bieniek K 139 , Durda K 138 , Sukiennicki G 138 , Huzarski T 138 , Byrski T 138 , Cybulski C 138 , Toloczko-Grabarek A 138 , Złowocka-Perłowska E 138 , Menkiszak J 140 , Arason A 141 , Barkardottir RB 141 , Simard J 142 , Laframboise R 143 , Montagna M 144 , Agata S 144 , Alducci E 144 , Peixoto A 145 , Teixeira MR 146 , Spurdle AB 4 , Lee MH 147 , Park SK 148 , Kim SW 149 , Friebel TM 2 , Couch FJ 150 , Lindor NM 151 , Pankratz VS 151 , Guidugli L 152 , Wang X 152 , Tischkowitz M 153 , Foretova L 154 , Vijai J 155 , Offit K 155 , Robson M 156 , Rau-Murthy R 156 , Kauff N 156 , Fink-Retter A 157 , Singer CF 157 , Rappaport C 157 , Gschwantler-Kaulich D 157 , Pfeiler G 157 , Tea MK 157 , Berger A 157 , Greene MH 158 , Mai PL 158 , Imyanitov EN 159 , Toland AE 160 , Senter L 161 , Bojesen A 162 , Pedersen IS 163 , Skytte AB 162 , Sunde L 164 , Thomassen M 165 , Moeller ST 165 , Kruse TA 165 , Jensen UB 164 , Caligo MA 166 , Aretini P 166 , Teo SH 167 , Selkirk CG 168 , Hulick PJ 168 , Andrulis I 169

Affiliations 

  • 1 Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia2Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 2 Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 3 Centre de Recherche en Cancérologie de Lyon, UMR Inserm, Centre Léon Bérard, Lyon, France
  • 4 Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia
  • 5 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 6 Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia6Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 7 Sheba Medical Center, Tel Aviv, Israel
  • 8 Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Israel
  • 9 Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel
  • 10 Oncology Institute, Rivkah Ziv Medical Center Zefat, Israel
  • 11 Department of Oncology, Lund University, Lund, Sweden12Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  • 12 Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  • 13 Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
  • 14 Department of Oncology, Lund University, Lund, Sweden
  • 15 Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
  • 16 Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
  • 17 Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois
  • 18 UCLA Schools of Medicine and Public Health, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California
  • 19 Department of Medicine and Genetics, University of California, San Francisco
  • 20 Cancer Risk Program, Helen Diller Family Cancer Center, University of California, San Francisco
  • 21 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York
  • 22 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles
  • 23 University of Texas MD Anderson Cancer Center, Houston
  • 24 Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 25Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
  • 25 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
  • 26 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City
  • 27 Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 28 Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California
  • 29 Department of Epidemiology, Cancer Prevention Institute of California, Fremont
  • 30 Dana-Farber Cancer Institute, Boston, Massachusetts
  • 31 Department of Epidemiology, Columbia University, New York, New York
  • 32 Departments of Pediatrics and Medicine, Columbia University, New York, New York
  • 33 Department of Dermatology, University of Utah School of Medicine, Salt Lake City
  • 34 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City
  • 35 Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology, and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, State Research Institute Innovative Medicine Center, Vilnius, Lithuania
  • 36 Latvian Biomedical Research and Study Centre, Riga, Latvia
  • 37 Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 38 Department of Genetics, University of Pretoria, Pretoria, South Africa
  • 39 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California
  • 40 Departments of Oncology or Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 41 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 42 Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  • 43 Human Genetics Group, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain
  • 44 Human Genetics Group and Genotyping Unit, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain
  • 45 Hospital clinico Universitario "Lozano Blesa," Instituto de investigación sanitaria de Aragón (IIS), Zaragoza, Spain
  • 46 Molecular Genetics Laboratory (Department of Genetics), Cruces University Hospital Barakaldo, Bizkaia, Spain
  • 47 Institute of Biology and Molecular Genetics. Universidad de Valladolid (IBGM-UVA), Valladolid, Spain
  • 48 Clinical Cancer Genetics, City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California
  • 49 Unit of Genetic Counselling, Medical Oncology Department, Istituto Nazionale Tumori Regina Elena, Rome, Italy
  • 50 Department of Medical Science, University of Turin, and AO Città della Salute e della Scienza, Turin, Italy
  • 51 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 52 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy
  • 53 AO Città della Salute e della Scienza, Turin, Italy
  • 54 Department of Molecular Medicine, University La Sapienza, Rome, Italy
  • 55 Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy57Cogentech Cancer Genetic Test Laboratory, Milan, Italy
  • 56 Institute of Medical Genetics, Catholic University, "A. Gemelli" Hospital, Rome, Italy
  • 57 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy60IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
  • 58 Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, IRCCSCRO Aviano National Cancer Institute, Aviano (PN), Italy
  • 59 Cogentech Cancer Genetic Test Laboratory, Milan, Italy60IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
  • 60 Unit of Hereditary Cancer, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
  • 61 Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos" Aghia Paraskevi Attikis, Athens, Greece
  • 62 Instituto de Genética Humana, Pontificia Universidad Javeriana, Bogotá, Colombia65Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
  • 63 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany 66Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
  • 64 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
  • 65 Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals, NHS Foundation Trust, Manchester, United Kingdom
  • 66 Oncogenetics Team, Institute of Cancer Research and Royal Marsden, NHS Foundation Trust, London, United Kingdom
  • 67 Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom
  • 68 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom
  • 69 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom
  • 70 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom
  • 71 Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, United Kingdom
  • 72 Clinical Genetics Department, St Georges Hospital, University of London, United Kingdom
  • 73 Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom
  • 74 Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom
  • 75 South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom
  • 76 Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire
  • 77 South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom
  • 78 Yorkshire Regional Genetics Service, Leeds, United Kingdom
  • 79 South West Regional Genetics Service, Bristol, United Kingdom
  • 80 Department of Hematology and Oncology, University of Kansas Medical Center, Kansas City
  • 81 Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), and Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany
  • 82 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  • 83 Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
  • 84 Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
  • 85 Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
  • 86 Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
  • 87 Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
  • 88 Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
  • 89 Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany
  • 90 Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
  • 91 Institute of Human Genetics, Technical University Dresden, Dresden, Germany
  • 92 Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany
  • 93 Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University of Würzburg, Würzburg, Germany
  • 94 Institute of Human Genetics, University of Regensburg, Regensburg, Germany
  • 95 Institut Curie, Department of Tumour Biology, Paris, France98Institut Curie, INSERM U830, Paris, France99Université Paris Descartes, Sorbonne Paris Cité, France
  • 96 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon-Centre Léon Bérard, Lyon, France101INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France
  • 97 INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France
  • 98 Institut Curie, Department of Tumour Biology, Paris, France99Université Paris Descartes, Sorbonne Paris Cité, France
  • 99 Institut Curie, Department of Tumour Biology, Paris, France
  • 100 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon-Centre Léon Bérard, Lyon, France
  • 101 Université Lyon 1, CNRS UMR5558, Lyon, France103Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France
  • 102 Département Oncologie Génétique, Prévention et Dépistage, INSERM CIC-P9502, Institut Paoli-Calmettes/Université d'Aix-Marseille II, Marseille, France
  • 103 Laboratoire d'Oncologie Moléculaire Humaine, Centre Oscar Lambret, Lille, France
  • 104 Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France
  • 105 Service de Génétique Biologique-Histologie-Biologie du Développement et de la Reproduction, Centre Hospitalier Universitaire de Besançon, Besançon, France
  • 106 Service de Génétique, Centre Hospitalier Universitaire Bretonneau, Tours, France
  • 107 Oncogénétique Clinique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France
  • 108 Laboratoire d'Oncogénétique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France
  • 109 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
  • 110 Center for Medical Genetics, Ghent University, Ghent, Belgium
  • 111 GOG Statistical and Data Center, Buffalo, New York
  • 112 Evanston Hospital, Evanston, Illinois
  • 113 Tufts University, Medford, Massachusetts
  • 114 University of North Carolina, Chapel Hill
  • 115 New York University, New York, New York
  • 116 Ohio State, Good Samaritan Hospital, Cincinnati
  • 117 Yale University School of Medicine, New Haven, Connecticut
  • 118 Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
  • 119 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
  • 120 Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland
  • 121 Department of Genetics, University Medical Center, Groningen University, Groningen, The Netherlands
  • 122 Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands
  • 123 Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 124 Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 125 Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands
  • 126 Department of Human Genetics and Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  • 127 Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands
  • 128 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • 129 Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  • 130 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
  • 131 Department of Human Genetics and Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  • 132 Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong135Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong136Department of Surgery, University of Hong Kong, Hong Kong
  • 133 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  • 134 Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain139University Hospital of Vall d'Hebron, Barcelona, Spain
  • 135 Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain
  • 136 Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI-Catalan Institute of Oncology, Girona, Spain
  • 137 Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain
  • 138 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 139 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland144Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland
  • 140 Department of Surgical Gynecology and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
  • 141 Department of Pathology, Landspitali University Hospital, Reykjavík, Iceland147BMC, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  • 142 Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Quebec City, Quebec, Canada149Laval University, Quebec City, Quebec, Canada
  • 143 Medical Genetics Division, Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada151Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
  • 144 Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
  • 145 Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
  • 146 Department of Genetics, Portuguese Oncology Institute, Porto, Portugal153Biomedical Sciences Institute (ICBAS), University of Porto, Portugal
  • 147 Department of Surgery, Soonchunhyang University and Hospital, Seoul, Korea
  • 148 Department of Preventive Medicine, Seoul National University College of Medicine and Cancer Research Institute, Seoul National University, Seoul, Korea
  • 149 Department of Surgery, Daerim St Mary's Hospital, Seoul, Korea
  • 150 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota159Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 151 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 152 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 153 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada161Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
  • 154 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic
  • 155 Clinical Genetics Service, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York
  • 156 Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York
  • 157 Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 158 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
  • 159 N. N. Petrov Institute of Oncology, St Petersburg, Russia
  • 160 Divison of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus
  • 161 Divison of Human Genetics, Department of Internal Medicine, Comprehensive Cancer Center, Ohio State University, Columbus
  • 162 Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark
  • 163 Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
  • 164 Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark
  • 165 Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
  • 166 Section of Genetic Oncology, Department of Oncology, University of Pisa and University Hospital of Pisa, Pisa, Italy
  • 167 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia176Department of Surgery, Faculty of Medicine, University Malaya Cancer Research Institute, University Malaya, Kuala Lumpur, Malaysia
  • 168 NorthShore University HealthSystem, Department of Medicine, Evanston, Illinois
  • 169 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada
JAMA, 2015 Apr 07;313(13):1347-61.
PMID: 25849179 DOI: 10.1001/jama.2014.5985

Abstract

IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.

OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2.

DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.

EXPOSURES: Mutations of BRCA1 or BRCA2.

MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.

RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.

CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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