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    JAMA. 2015 Apr 8. pii: 2214084. doi: 10.1001/jama.2014.5985. pmc: PMC4537700. mid: NIHMS693111
    Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
    Rebbeck TR1,  Mitra N2,  Wan F3,  Sinilnikova OM4,  Healey S5,  McGuffog L6,  Mazoyer S7,  Chenevix-Trench G8,  Easton DF9,  Antoniou AC10,  Nathanson KL11,  Laitman Y12,  Kushnir A13,  Paluch-Shimon S14,  Berger R15,  Zidan J16,  Friedman E17,  Ehrencrona H18,  Stenmark-Askmalm M19,  Einbeigi Z20,  Loman N21,  Harbst K22,  Rantala J23,  Melin B24,  Huo D25,  Olopade OI26,  Seldon J27,  Ganz PA28,  Nussbaum RL29,  Chan SB30,  Odunsi K31,  Gayther SA32,  Domchek SM33,  Arun BK34,  Lu KH35,  Mitchell G36,  Karlan BY37,  Walsh C38,  Lester J39,  Godwin AK40,  Pathak H41,  Ross E42,  Daly MB43,  Whittemore AS44,  John EM45,  Miron A46,  Terry MB47,  Chung WK48,  Goldgar DE49,  Buys SS50,  Janavicius R51,  Tihomirova L52,  Tung N53,  Dorfling CM54,  van Rensburg EJ55,  Steele L56,  Neuhausen SL57,  Ding YC58,  Ejlertsen B59,  Gerdes AM60,  Hansen Tv61,  Ramón y Cajal T62,  Osorio A63,  Benitez J64,  Godino J65,  Tejada MI66,  Duran M67,  Weitzel JN68,  Bobolis KA69,  Sand SR70,  Fontaine A71,  Savarese A72,  Pasini B73,  Peissel B74,  Bonanni B75,  Zaffaroni D76,  Vignolo-Lutati F77,  Scuvera G78,  Giannini G79,  Bernard L80,  Genuardi M81,  Radice P82,  Dolcetti R83,  Manoukian S84,  Pensotti V85,  Gismondi V86,  Yannoukakos D87,  Fostira F88,  Garber J89,  Torres D90,  Rashid MU91,  Hamann U92,  Peock S93,  Frost D94,  Platte R95,  Evans DG96,  Eeles R97,  Davidson R98,  Eccles D99,  Cole T100,  Cook J101,  Brewer C102,  Hodgson S103,  Morrison PJ104,  Walker L105,  Porteous ME106,  Kennedy MJ107,  Izatt L108,  Adlard J109,  Donaldson A110,  Ellis S111,  Sharma P112,  Schmutzler RK113,  Wappenschmidt B114,  Becker A115,  Rhiem K116,  Hahnen E117,  Engel C118,  Meindl A119,  Engert S120,  Ditsch N121,  Arnold N122,  Plendl HJ123,  Mundhenke C124,  Niederacher D125,  Fleisch M126,  Sutter C127,  Bartram CR128,  Dikow N129,  Wang-Gohrke S130,  Gadzicki D131,  Steinemann D132,  Kast K133,  Beer M134,  Varon-Mateeva R135,  Gehrig A136,  Weber BH137,  Stoppa-Lyonnet D138,  Sinilnikova OM139,  Mazoyer S140,  Houdayer C141,  Belotti M142,  Gauthier-Villars M143,  Damiola F144,  Boutry-Kryza N145,  Lasset C146,  Sobol H147,  Peyrat JP148,  Muller D149,  Fricker JP150,  Collonge-Rame MA151,  Mortemousque I152,  Nogues C153,  Rouleau E154,  Isaacs C155,  De Paepe A156,  Poppe B157,  Claes K158,  De Leeneer K159,  Piedmonte M160,  Rodriguez G161,  Wakely K162,  Boggess J163,  Blank SV164,  Basil J165,  Azodi M166,  Phillips KA167,  Caldes T168,  de la Hoya M169,  Romero A170,  Nevanlinna H171,  Aittomäki K172,  van der Hout AH173,  Hogervorst FB174,  Verhoef S175,  Collée JM176,  Seynaeve C177,  Oosterwijk JC178,  Gille JJ179,  Wijnen JT180,  Gómez Garcia EB181,  Kets CM182,  Ausems MG183,  Aalfs CM184,  Devilee P185,  Mensenkamp AR186,  Kwong A187,  Olah E188,  Papp J189,  Diez O190,  Lazaro C191,  Darder E192,  Blanco I193,  Salinas M194,  Jakubowska A195,  Lubinski J196,  Gronwald J197,  Jaworska-Bieniek K198,  Durda K199,  Sukiennicki G200,  Huzarski T201,  Byrski T202,  Cybulski C203,  Toloczko-Grabarek A204,  Złowocka-Perłowska E205,  Menkiszak J206,  Arason A207,  Barkardottir RB208,  Simard J209,  Laframboise R210,  Montagna M211,  Agata S212,  Alducci E213,  Peixoto A214,  Teixeira MR215,  Spurdle AB216,  Lee MH217,  Park SK218,  Kim SW219,  Friebel TM220,  Couch FJ221,  Lindor NM222,  Pankratz VS223,  Guidugli L224,  Wang X225,  Tischkowitz M226,  Foretova L227,  Vijai J228,  Offit K229,  Robson M230,  Rau-Murthy R231,  Kauff N232,  Fink-Retter A233,  Singer CF234,  Rappaport C235,  Gschwantler-Kaulich D236,  Pfeiler G237,  Tea MK238,  Berger A239,  Greene MH240,  Mai PL241,  Imyanitov EN242,  Toland AE243,  Senter L244,  Bojesen A245,  Pedersen IS246,  Skytte AB247,  Sunde L248,  Thomassen M249,  Moeller ST250,  Kruse TA251,  Jensen UB252,  Caligo MA253,  Aretini P254,  Teo SH255,  Selkirk CG256,  Hulick PJ257,  Andrulis I258
    Author information
    1Abramson 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.
    2Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
    3Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
    4Unité 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.
    5Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
    6Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    7INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
    8Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
    9Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    10Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    11Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia6Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
    12Sheba Medical Center, Tel Aviv, Israel.
    13Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Israel.
    14Sheba Medical Center, Tel Aviv, Israel.
    15Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel.
    16Oncology Institute, Rivkah Ziv Medical Center Zefat, Israel.
    17Sheba Medical Center, Tel Aviv, Israel.
    18Department of Oncology, Lund University, Lund, Sweden12Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    19Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    20Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    21Department of Oncology, Lund University, Lund, Sweden.
    22Department of Oncology, Lund University, Lund, Sweden.
    23Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
    24Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    25Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois.
    26Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois.
    27UCLA Schools of Medicine and Public Health, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California.
    28UCLA Schools of Medicine and Public Health, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California.
    29Department of Medicine and Genetics, University of California, San Francisco.
    30Cancer Risk Program, Helen Diller Family Cancer Center, University of California, San Francisco.
    31Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York.
    32Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
    33Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia6Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
    34University of Texas MD Anderson Cancer Center, Houston.
    35University of Texas MD Anderson Cancer Center, Houston.
    36Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 25Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
    37Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
    38Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
    39Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
    40Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City.
    41Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City.
    42Fox Chase Cancer Center, Philadelphia, Pennsylvania.
    43Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California.
    44Cancer Risk Program, Helen Diller Family Cancer Center, University of California, San Francisco.
    45Department of Epidemiology, Cancer Prevention Institute of California, Fremont.
    46Dana-Farber Cancer Institute, Boston, Massachusetts.
    47Department of Epidemiology, Columbia University, New York, New York.
    48Departments of Pediatrics and Medicine, Columbia University, New York, New York.
    49Department of Dermatology, University of Utah School of Medicine, Salt Lake City.
    50Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City.
    51Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology, and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, State Research Institute Innovative Medicine Center, Vilnius, Lithuania.
    52Latvian Biomedical Research and Study Centre, Riga, Latvia.
    53Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
    54Department of Genetics, University of Pretoria, Pretoria, South Africa.
    55Department of Genetics, University of Pretoria, Pretoria, South Africa.
    56Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California.
    57Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California.
    58Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California.
    59Departments of Oncology or Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    60Departments of Oncology or Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    61Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    62Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
    63Human Genetics Group, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
    64Human Genetics Group and Genotyping Unit, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
    65Hospital clinico Universitario "Lozano Blesa," Instituto de investigación sanitaria de Aragón (IIS), Zaragoza, Spain.
    66Molecular Genetics Laboratory (Department of Genetics), Cruces University Hospital Barakaldo, Bizkaia, Spain.
    67Institute of Biology and Molecular Genetics. Universidad de Valladolid (IBGM-UVA), Valladolid, Spain.
    68Clinical Cancer Genetics, City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California.
    69Clinical Cancer Genetics, City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California.
    70Clinical Cancer Genetics, City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California.
    71Clinical Cancer Genetics, City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California.
    72Unit of Genetic Counselling, Medical Oncology Department, Istituto Nazionale Tumori Regina Elena, Rome, Italy.
    73Department of Medical Science, University of Turin, and AO Città della Salute e della Scienza, Turin, Italy.
    74Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
    75Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
    76Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
    77AO Città della Salute e della Scienza, Turin, Italy.
    78Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
    79Department of Molecular Medicine, University La Sapienza, Rome, Italy.
    80Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy57Cogentech Cancer Genetic Test Laboratory, Milan, Italy.
    81Institute of Medical Genetics, Catholic University, "A. Gemelli" Hospital, Rome, Italy.
    82Unit 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.
    83Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, IRCCSCRO Aviano National Cancer Institute, Aviano (PN), Italy.
    84Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
    85Cogentech Cancer Genetic Test Laboratory, Milan, Italy60IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
    86Unit of Hereditary Cancer, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
    87Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos" Aghia Paraskevi Attikis, Athens, Greece.
    88Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos" Aghia Paraskevi Attikis, Athens, Greece.
    89Dana-Farber Cancer Institute, Boston, Massachusetts.
    90Instituto de Genética Humana, Pontificia Universidad Javeriana, Bogotá, Colombia65Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
    91Molecular 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.
    92Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
    93Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    94Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    95Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    96Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals, NHS Foundation Trust, Manchester, United Kingdom.
    97Oncogenetics Team, Institute of Cancer Research and Royal Marsden, NHS Foundation Trust, London, United Kingdom.
    98Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom.
    99Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.
    100West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom.
    101Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom.
    102Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, United Kingdom.
    103Clinical Genetics Department, St Georges Hospital, University of London, United Kingdom.
    104Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom.
    105Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom.
    106South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom.
    107Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire.
    108South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom.
    109Yorkshire Regional Genetics Service, Leeds, United Kingdom.
    110South West Regional Genetics Service, Bristol, United Kingdom.
    111Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    112Department of Hematology and Oncology, University of Kansas Medical Center, Kansas City.
    113Center 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.
    114Center 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.
    115Center 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.
    116Center 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.
    117Center 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.
    118Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
    119Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
    120Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
    121Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
    122Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany.
    123Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany.
    124Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany.
    125Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
    126Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
    127Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
    128Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
    129Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
    130Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
    131Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
    132Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
    133Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
    134Institute of Human Genetics, Technical University Dresden, Dresden, Germany.
    135Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany.
    136Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
    137Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
    138Institut Curie, Department of Tumour Biology, Paris, France98Institut Curie, INSERM U830, Paris, France99Université Paris Descartes, Sorbonne Paris Cité, France.
    139Unité 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.
    140INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
    141Institut Curie, Department of Tumour Biology, Paris, France99Université Paris Descartes, Sorbonne Paris Cité, France.
    142Institut Curie, Department of Tumour Biology, Paris, France.
    143Institut Curie, Department of Tumour Biology, Paris, France.
    144INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
    145Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon-Centre Léon Bérard, Lyon, France.
    146Université Lyon 1, CNRS UMR5558, Lyon, France103Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.
    147Département Oncologie Génétique, Prévention et Dépistage, INSERM CIC-P9502, Institut Paoli-Calmettes/Université d'Aix-Marseille II, Marseille, France.
    148Laboratoire d'Oncologie Moléculaire Humaine, Centre Oscar Lambret, Lille, France.
    149Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France.
    150Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France.
    151Service de Génétique Biologique-Histologie-Biologie du Développement et de la Reproduction, Centre Hospitalier Universitaire de Besançon, Besançon, France.
    152Service de Génétique, Centre Hospitalier Universitaire Bretonneau, Tours, France.
    153Oncogénétique Clinique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France.
    154Laboratoire d'Oncogénétique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France.
    155Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
    156Center for Medical Genetics, Ghent University, Ghent, Belgium.
    157Center for Medical Genetics, Ghent University, Ghent, Belgium.
    158Center for Medical Genetics, Ghent University, Ghent, Belgium.
    159Center for Medical Genetics, Ghent University, Ghent, Belgium.
    160GOG Statistical and Data Center, Buffalo, New York.
    161Evanston Hospital, Evanston, Illinois.
    162Tufts University, Medford, Massachusetts.
    163University of North Carolina, Chapel Hill.
    164New York University, New York, New York.
    165Ohio State, Good Samaritan Hospital, Cincinnati.
    166Yale University School of Medicine, New Haven, Connecticut.
    167Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 25Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
    168Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain.
    169Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain.
    170Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain.
    171Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    172Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
    173Department of Genetics, University Medical Center, Groningen University, Groningen, The Netherlands.
    174Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
    175Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
    176Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
    177Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
    178Department of Genetics, University Medical Center, Groningen University, Groningen, The Netherlands.
    179Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.
    180Department of Human Genetics and Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    181Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands.
    182Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
    183Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
    184Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
    185Department of Human Genetics and Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
    186Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
    187Hong 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.
    188Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    189Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    190Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain139University Hospital of Vall d'Hebron, Barcelona, Spain.
    191Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.
    192Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI-Catalan Institute of Oncology, Girona, Spain.
    193Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.
    194Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.
    195Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    196Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    197Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    198Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland144Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland.
    199Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    200Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    201Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    202Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    203Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    204Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    205Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    206Department of Surgical Gynecology and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland.
    207Department of Pathology, Landspitali University Hospital, Reykjavík, Iceland147BMC, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    208Department of Pathology, Landspitali University Hospital, Reykjavík, Iceland147BMC, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    209Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Quebec City, Quebec, Canada149Laval University, Quebec City, Quebec, Canada.
    210Medical Genetics Division, Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada151Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy.
    211Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy.
    212Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy.
    213Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy.
    214Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
    215Department of Genetics, Portuguese Oncology Institute, Porto, Portugal153Biomedical Sciences Institute (ICBAS), University of Porto, Portugal.
    216Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
    217Department of Surgery, Soonchunhyang University and Hospital, Seoul, Korea.
    218Department of Preventive Medicine, Seoul National University College of Medicine and Cancer Research Institute, Seoul National University, Seoul, Korea.
    219Department of Surgery, Daerim St Mary's Hospital, Seoul, Korea.
    220Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
    221Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota159Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
    222Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
    223Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
    224Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
    225Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
    226Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada161Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
    227Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic.
    228Clinical Genetics Service, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
    229Clinical Genetics Service, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
    230Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York.
    231Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York.
    232Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York.
    233Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    234Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    235Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    236Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    237Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    238Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    239Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    240Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
    241Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
    242N. N. Petrov Institute of Oncology, St Petersburg, Russia.
    243Divison of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus.
    244Divison of Human Genetics, Department of Internal Medicine, Comprehensive Cancer Center, Ohio State University, Columbus.
    245Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
    246Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
    247Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
    248Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
    249Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
    250Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
    251Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
    252Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
    253Section of Genetic Oncology, Department of Oncology, University of Pisa and University Hospital of Pisa, Pisa, Italy.
    254Section of Genetic Oncology, Department of Oncology, University of Pisa and University Hospital of Pisa, Pisa, Italy.
    255Cancer 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.
    256NorthShore University HealthSystem, Department of Medicine, Evanston, Illinois.
    257NorthShore University HealthSystem, Department of Medicine, Evanston, Illinois.
    258Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
    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.


    Publikations ID: 25849179
    Quelle: öffnen
     
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