Timothy R Rebbeck1, Nandita Mitra2, Fei Wan2, Olga M Sinilnikova96, Sue Healey4, Lesley McGuffog5, Sylvie Mazoyer97, Georgia Chenevix-Trench4, Douglas F Easton5, Antonis C Antoniou5, Katherine L Nathanson6, Yael Laitman7, Anya Kushnir8, Shani Paluch-Shimon7, Raanan Berger9, Jamal Zidan10, Eitan Friedman7, Hans Ehrencrona11, Marie Stenmark-Askmalm12, Zakaria Einbeigi13, Niklas Loman14, Katja Harbst14, Johanna Rantala15, Beatrice Melin16, Dezheng Huo17, Olufunmilayo I Olopade17, Joyce Seldon18, Patricia A Ganz18, Robert L Nussbaum19, Salina B Chan20, Kunle Odunsi21, Simon A Gayther22, Susan M Domchek6, Banu K Arun23, Karen H Lu23, Gillian Mitchell24, Beth Y Karlan25, Christine Walsh25, Jenny Lester25, Andrew K Godwin26, Harsh Pathak26, Eric Ross27, Mary B Daly28, Alice S Whittemore20, Esther M John29, Alexander Miron30, Mary Beth Terry31, Wendy K Chung32, David E Goldgar33, Saundra S Buys34, Ramunas Janavicius35, Laima Tihomirova36, Nadine Tung37, Cecilia M Dorfling38, Elizabeth J van Rensburg38, Linda Steele39, Susan L Neuhausen39, Yuan Chun Ding39, Bent Ejlertsen40, Anne-Marie Gerdes40, Thomas v O Hansen41, Teresa Ramón y Cajal42, Ana Osorio43, Javier Benitez44, Javier Godino45, Maria-Isabel Tejada46, Mercedes Duran47, Jeffrey N Weitzel48, Kristie A Bobolis48, Sharon R Sand48, Annette Fontaine48, Antonella Savarese49, Barbara Pasini50, Bernard Peissel51, Bernardo Bonanni52, Daniela Zaffaroni51, Francesca Vignolo-Lutati53, Giulietta Scuvera51, Giuseppe Giannini54, Loris Bernard55, Maurizio Genuardi56, Paolo Radice57, Riccardo Dolcetti58, Siranoush Manoukian51, Valeria Pensotti59, Viviana Gismondi60, Drakoulis Yannoukakos61, Florentia Fostira61, Judy Garber30, Diana Torres62, Muhammad Usman Rashid63, Ute Hamann64, Susan Peock5, Debra Frost5, Radka Platte5, D Gareth Evans65, Rosalind Eeles66, Rosemarie Davidson67, Diana Eccles68, Trevor Cole69, Jackie Cook70, Carole Brewer71, Shirley Hodgson72, Patrick J Morrison73, Lisa Walker74, Mary E Porteous75, M John Kennedy76, Louise Izatt77, Julian Adlard78, Alan Donaldson79, Steve Ellis5, Priyanka Sharma80, Rita Katharina Schmutzler81, Barbara Wappenschmidt81, Alexandra Becker81, Kerstin Rhiem81, Eric Hahnen81, Christoph Engel82, Alfons Meindl83, Stefanie Engert83, Nina Ditsch83, Norbert Arnold84, Hans Jörg Plendl85, Christoph Mundhenke84, Dieter Niederacher86, Markus Fleisch86, Christian Sutter87, C R Bartram87, Nicola Dikow87, Shan Wang-Gohrke88, Dorothea Gadzicki89, Doris Steinemann89, Karin Kast90, Marit Beer91, Raymonda Varon-Mateeva92, Andrea Gehrig93, Bernhard H Weber94, Dominique Stoppa-Lyonnet95, Olga M Sinilnikova96, Sylvie Mazoyer97, Claude Houdayer98, Muriel Belotti99, Marion Gauthier-Villars99, Francesca Damiola97, Nadia Boutry-Kryza100, Christine Lasset101, Hagay Sobol102, Jean-Philippe Peyrat103, Danièle Muller104, Jean-Pierre Fricker104, Marie-Agnès Collonge-Rame105, Isabelle Mortemousque106, Catherine Nogues107, Etienne Rouleau108, Claudine Isaacs109, Anne De Paepe110, Bruce Poppe110, Kathleen Claes110, Kim De Leeneer110, Marion Piedmonte111, Gustavo Rodriguez112, Katie Wakely113, John Boggess114, Stephanie V Blank115, Jack Basil116, Masoud Azodi117, Kelly-Anne Phillips24, Trinidad Caldes118, Miguel de la Hoya118, Atocha Romero118, Heli Nevanlinna119, Kristiina Aittomäki120, Annemarie H van der Hout121, Frans B L Hogervorst122, Senno Verhoef122, J Margriet Collée123, Caroline Seynaeve124, Jan C Oosterwijk121, Johannes J P Gille125, Juul T Wijnen126, Encarna B Gómez Garcia127, Carolien M Kets128, Margreet G E M Ausems129, Cora M Aalfs130, Peter Devilee131, Arjen R Mensenkamp128, Ava Kwong132, Edith Olah133, Janos Papp133, Orland Diez134, Conxi Lazaro135, Esther Darder136, Ignacio Blanco137, Mónica Salinas137, Anna Jakubowska138, Jan Lubinski138, Jacek Gronwald138, Katarzyna Jaworska-Bieniek139, Katarzyna Durda138, Grzegorz Sukiennicki138, Tomasz Huzarski138, Tomasz Byrski138, Cezary Cybulski138, Aleksandra Toloczko-Grabarek138, Elżbieta Złowocka-Perłowska138, Janusz Menkiszak140, Adalgeir Arason141, Rosa B Barkardottir141, Jacques Simard142, Rachel Laframboise143, Marco Montagna144, Simona Agata144, Elisa Alducci144, Ana Peixoto145, Manuel R Teixeira146, Amanda B Spurdle4, Min Hyuk Lee147, Sue K Park148, Sung-Won Kim149, Tara M Friebel2, Fergus J Couch150, Noralane M Lindor151, Vernon S Pankratz151, Lucia Guidugli152, Xianshu Wang152, Marc Tischkowitz153, Lenka Foretova154, Joseph Vijai155, Kenneth Offit155, Mark Robson156, Rohini Rau-Murthy156, Noah Kauff156, Anneliese Fink-Retter157, Christian F Singer157, Christine Rappaport157, Daphne Gschwantler-Kaulich157, Georg Pfeiler157, Muy-Kheng Tea157, Andreas Berger157, Mark H Greene158, Phuong L Mai158, Evgeny N Imyanitov159, Amanda Ewart Toland160, Leigha Senter161, Anders Bojesen162, Inge Sokilde Pedersen163, Anne-Bine Skytte162, Lone Sunde164, Mads Thomassen165, Sanne Traasdahl Moeller165, Torben A Kruse165, Uffe Birk Jensen164, Maria Adelaide Caligo166, Paolo Aretini166, Soo-Hwang Teo167, Christina G Selkirk168, Peter J Hulick168, Irene Andrulis169. 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.
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.
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.
Authors: David E Goldgar; Douglas F Easton; Amie M Deffenbaugh; Alvaro N A Monteiro; Sean V Tavtigian; Fergus J Couch Journal: Am J Hum Genet Date: 2004-08-02 Impact factor: 11.025
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