Mutational spectrum in a worldwide study of 29,700 families with<i>BRCA1</i>or<i>BRCA2</i>mutations
Timothy R. Rebbeck(Boston University), Tara M. Friebel(Boston University), Eitan Friedman(Tel Aviv University), Ute Hamann(German Cancer Research Center), Dezheng Huo(University of Chicago), Ava Kwong(Hong Kong Sanatorium and Hospital), Edith Oláh(National Institute of Oncology), Olufunmilayo I. Olopade(University of Chicago), Ángela R. Solano(Consejo Nacional de Investigaciones Científicas y Técnicas), Soo‐Hwang Teo(Cancer Research Malaysia), Mads Thomassen(Odense University Hospital), Jeffrey N. Weitzel(City of Hope), TL Chan(Hong Kong Sanatorium and Hospital), Fergus J. Couch, David E. Goldgar(University of Utah), Torben A. Kruse(Odense University Hospital), Edenir Inêz Palmero(Hospital de Câncer de Barretos), Sue K. Park(Seoul National University), Diana Torres(German Cancer Research Center), Elizabeth J. van Rensburg(University of Pretoria), Lesley McGuffog(University of Cambridge), Michael T. Parsons(QIMR Berghofer Medical Research Institute), Goska Leslie(University of Cambridge), Cora M. Aalfs(Amsterdam UMC Location University of Amsterdam), Julio E. Abugattas(City of Hope), Julian Adlard(Chapel Allerton Hospital), Simona Agata(Istituto Oncologico Veneto), Kristiina Aittomäki(University of Helsinki), Lesley Andrews(Prince of Wales Hospital), Irene L. Andrulis(University of Toronto), Aðalgeir Arason(University of Iceland), Norbert Arnold(Medical University of Vienna), Banu Arun(The University of Texas MD Anderson Cancer Center), Ella Asseryanis(Comprehensive Cancer Center Vienna), Leo Auerbach(Comprehensive Cancer Center Vienna), Jacopo Azzollini(Fondazione IRCCS Istituto Nazionale dei Tumori), Judith Balmañà(Vall d'Hebron Hospital Universitari), Monica Barile(European Institute of Oncology), Rósa B. Barkardóttir(University of Iceland), Daniel Barrowdale(University of Cambridge), Javier Benı́tez(Spanish National Cancer Research Centre), Andreas Berger(Comprehensive Cancer Center Vienna), Raanan Berger(Sheba Medical Center), Amie Blanco(Cancer Genetics (United States)), Kathleen R. Blazer(City of Hope), Marinus J. Blok(Maastricht University), Valérie Bonadona(Centre Léon Bérard), Bernardo Bonanni(European Institute of Oncology), Angela R. Bradbury(University of Pennsylvania), Carole Brewer(Royal Devon and Exeter Hospital), Bruno Buecher(Institut Curie), Saundra S. Buys(Huntsman Cancer Institute), Trinidad Caldés(Hospital Clínico San Carlos), Almuth Caliebe(University Hospital Schleswig-Holstein), Maria A. Caligo(Azienda Ospedaliera Universitaria Pisana), Ian Campbell(Peter MacCallum Cancer Centre), Sandrine M. Caputo(Institut Curie), Jocelyne Chiquette(Hôpital du Saint-Sacrement), Wendy K. Chung(Columbia University), Kathleen Claes(Ghent University), J. Margriet Collée(Erasmus MC), Jackie Cook(Sheffield Children's Hospital), Rosemarie Davidson, Miguel de la Hoya(Hospital Clínico San Carlos), Kim De Leeneer(Ghent University), Antoine De Pauw(Institut Curie), Capucine Delnatte(Institut Génétique Nantes Atlantique), Orland Dı́ez(Vall d'Hebron Hospital Universitari), Yuan Chun Ding(City of Hope), Nina Ditsch(Ludwig-Maximilians-Universität München), Susan M. Domchek(University of Pennsylvania), Cecilia M. Dorfling(University of Pretoria), Carolina Velázquez(Universidad de Valladolid), Bernd Dworniczak(University of Münster), Jacqueline Eason(Nottingham University Hospitals NHS Trust), Douglas F. Easton(University of Cambridge), Rosalind A. Eeles(Royal Marsden NHS Foundation Trust), Hans Ehrencrona(Lund University), Bent Ejlertsen(Copenhagen University Hospital), EMBRACE(Leipzig University), Christoph Engel(TUM Klinikum), Stefanie Engert(Manchester Academic Health Science Centre), D. Gareth Evans(Manchester Academic Health Science Centre), Laurence Faivre(Institut d'Investigació Biomédica de Bellvitge), Lídia Feliubadaló(Institut d'Investigació Biomédica de Bellvitge), Sandra Fert Ferrer(Masaryk Memorial Cancer Institute), Lenka Foretová(Columbus State University), Jeffrey M. Fowler(Columbus State University), Debra Frost(University of Cambridge), Henrique C.R. Galvão(Hospital de Câncer de Barretos), Patricia A. Ganz(Dana-Farber Cancer Institute), Judy E. Garber(Dana-Farber Cancer Institute), Marion Gauthier‐Villars(University of Würzburg), Andrea Gehrig(University of Würzburg), GEMO Study Collaborators(Centre Hospitalier de Niort), Anne‐Marie Gerdes(Istituto Pasteur), Paul Gesta(Centre Léon Bérard), Giuseppe Giannini(Mount Sinai Hospital), Sophie Giraud(Centre Léon Bérard), Gord Glendon(Mount Sinai Hospital), Andrew K. Godwin(University of Kansas Medical Center), Mark H. Greene(National Institutes of Health), Jacek Gronwald(University Hospital Cologne), Angelica M. Gutierrez‐Barrera(The University of Texas MD Anderson Cancer Center), Eric Hahnen(Centre for Life), Jan Hauke(University Hospital Cologne), HEBON(The Netherlands Cancer Institute), Alex Henderson(Centre for Life), Julia Hentschel(Institute of Oncology NN Petrov), Frans B. L. Hogervorst(Georgetown University), Ellen Honisch(Guy's and St Thomas' NHS Foundation Trust), Evgeny N. Imyanitov(Institut Català d'Oncologia), Claudine Isaacs(Georgetown University), Louise Izatt(Guy's and St Thomas' NHS Foundation Trust), Á. Izquierdo(Vilnius University), Anna Jakubowska(Aarhus University Hospital), Paul A. James(Cancer Prevention Institute of California), Ramūnas Janavičius(Memorial Sloan Kettering Cancer Center), Uffe Birk Jensen(Aarhus University Hospital), Esther M. John(Cedars-Sinai Medical Center), Joseph Vijai(Memorial Sloan Kettering Cancer Center), Katarzyna Kaczmarek(The University of Melbourne), Beth Y. Karlan(Cedars-Sinai Medical Center), Karin Kast(National Centre of Scientific Research "Demokritos"), kConFab Investigators(The University of Melbourne), Sung-Won Kim(Tel Aviv University), Irene Konstantopoulou(National Centre of Scientific Research "Demokritos"), Jacob Korach(Sheba Medical Center), Yael Laitman(Tel Aviv University), Adriana Lasa(Feinstein Institute for Medical Research), Christine Lasset(Soonchunhyang University Hospital Seoul), Conxi Lázaro(Cedars-Sinai Medical Center), Annette Lee(Feinstein Institute for Medical Research), Min Hyuk Lee(Karolinska University Hospital), Jenny Lester(Cedars-Sinai Medical Center), Fabienne Lesueur(Inserm), Annelie Liljegren(National Institutes of Health), Noralane M. Lindor(Mayo Clinic in Arizona), Michel Longy(Institut Bergonié), Jennifer T. Loud(National Institutes of Health), Karen H. Lu(Cancer Genetics (United States)), Jan Lubiński(Centre Antoine Lacassagne), Eva Macháčková(BioCruces Health research Institute), Siranoush Manoukian(National Institute of Oncology), Véronique Mari(Inserm), Cristina Martínez-Bouzas(BioCruces Health research Institute), Zoltán Mátrai(TUM Klinikum), Noura Mebirouk(Radboud University Nijmegen), Hanne Meijers‐Heijboer(Vilnius University Hospital Santariskiu Klinikos), Alfons Meindl(Roswell Park Comprehensive Cancer Center), Arjen R. Mensenkamp(Radboud University Nijmegen), Ugnius Mickys(Roswell Park Comprehensive Cancer Center), Austin Miller(Roswell Park Comprehensive Cancer Center), Marco Montagna(Memorial Sloan Kettering Cancer Center), Kirsten B. Moysich(Roswell Park Comprehensive Cancer Center), Anna Marie Mulligan(University of Helsinki), Jacob Musinsky(Memorial Sloan Kettering Cancer Center), Susan L. Neuhausen(City of Hope), Heli Nevanlinna(University of Helsinki), Joanne Ngeow(Odense University Hospital), Huu Phuc Nguyen(University of Copenhagen), Dieter Niederacher(University of California, San Francisco), Henriette Roed Nielsen(Memorial Sloan Kettering Cancer Center), Finn C. Nielsen(University of Copenhagen), Robert L. Nussbaum(University of California, San Francisco), Kenneth Offit(Memorial Sloan Kettering Cancer Center), Anna Öfverholm(Sahlgrenska University Hospital), Kai‐Ren Ong(Birmingham Women's Hospital), Ana Osório(Spanish National Cancer Research Centre), Laura Papi(Aalborg University Hospital), J. Papp(Universidade do Porto), Barbara Pasini(University of Turin), Inge Søkilde Pedersen(Aalborg University Hospital), Ana Peixoto(Universidade do Porto), Nina Peruga(Memorial Sloan Kettering Cancer Center), Paolo Peterlongo(IFOM), Esther Pohl(Hôpital Nord), Nisha Pradhan(Memorial Sloan Kettering Cancer Center), Karolina Prajzendanc(Fondazione IRCCS Istituto Nazionale dei Tumori), Fabienne Prieur(Garvan Institute of Medical Research), Pascal Pujol(Karolinska University Hospital), Paolo Radice(German Cancer Research Center), Susan J. Ramus(Garvan Institute of Medical Research), Johanna Rantala(Memorial Sloan Kettering Cancer Center), Muhammad Usman Rashid(NorthShore University HealthSystem), Kerstin Rhiem(University Hospital of Wales), Mark E. Robson(Memorial Sloan Kettering Cancer Center), Gustavo C. Rodriguez(University of Copenhagen), Mark T. Rogers(University Hospital of Wales), Vilius Rudaitis(Vilnius University), Ane Yde Schmidt(University of Copenhagen), Rita K. Schmutzler(University of Kansas Medical Center), Leigha Senter(Great Ormond Street Hospital), Payal D. Shah(Centre hospitalier universitaire de Québec), Priyanka Sharma(Comprehensive Cancer Center Vienna), Lucy Side(Great Ormond Street Hospital), Jacques Simard(Centre hospitalier universitaire de Québec), Christian F. Singer(St George's, University of London), Anne‐Bine Skytte(Aarhus University Hospital), Thomas P. Slavin(The University of Melbourne), Katie Snape(St George's, University of London), Hagay Sobol(Medizinische Hochschule Hannover), Melissa C. Southey(The University of Melbourne), Linda Steele(Heidelberg University), Doris Steinemann(National Institutes of Health), Grzegorz Sukiennicki(Comprehensive Cancer Center Vienna), Christian Sutter(Universidade do Porto), Csilla I. Szabo(National Institutes of Health), Yen Y. Tan(Institut d'Investigació Biomédica de Bellvitge), Manuel R. Teixeira(Universidade do Porto), Mary Beth Terry(University of Pittsburgh), Àlex Teulé(Institut d'Investigació Biomédica de Bellvitge), Abigail Thomas(Istituto Oncologico Veneto), Darcy L. Thull(University of Pittsburgh), Marc Tischkowitz(Memorial Sloan Kettering Cancer Center), Silvia Tognazzo(The Royal Melbourne Hospital), Amanda Ewart Toland(Beth Israel Deaconess Medical Center), Sabine Topka(Memorial Sloan Kettering Cancer Center), Alison H. Trainer(The Royal Melbourne Hospital), Nadine Tung(Beth Israel Deaconess Medical Center), Christi J. van Asperen(Leiden University Medical Center), Annemieke H. van der Hout(University Medical Center Groningen), Lizet E. van der Kolk(The Netherlands Cancer Institute), Rob B. van der Luijt(University Medical Center Utrecht), Mattias Van Heetvelde(Ghent University), Liliana Varesco(Hospital Zambrano Hellion), Raymonda Varon‐Mateeva(Karolinska University Hospital), Ana Vega(Churchill Hospital), Cynthia Villarreal‐Garza(Hospital Zambrano Hellion), Anna von Wachenfeldt(Karolinska University Hospital), Lisa Walker(Churchill Hospital), Shan Wang‐Gohrke(National Centre of Scientific Research "Demokritos"), Barbara Wappenschmidt(Cancer Research Malaysia), Bernhard H. F. Weber(Fondazione IRCCS Istituto Nazionale dei Tumori), Drakoulis Yannoukakos(National Centre of Scientific Research "Demokritos"), Sook-Yee Yoon(University of Pittsburgh), Cristina Zanzottera(NorthShore University HealthSystem), Jamal Zidan(NorthShore University HealthSystem), Kristin K. Zorn(University of Pittsburgh), Christina G. Selkirk(NorthShore University HealthSystem), Peter J. Hulick(NorthShore University HealthSystem), Georgia Chenevix‐Trench(QIMR Berghofer Medical Research Institute), Amanda B. Spurdle(QIMR Berghofer Medical Research Institute), Antonis C. Antoniou(University of Cambridge), Katherine L. Nathanson(University of Pennsylvania)
Cited by 312Open Access
Abstract
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
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