Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Timothy Rebbeck , Tara Friebel , Eitan Friedman , Ute Hamann , Dezheng Huo , Ava Kwong , Edith Olah , Olufunmilayo Olopade , Angela Solano , Soo-Hwang Teo , Mads Thomassen , Jeffrey Weitzel , Tl Chan , Fergus Couch , David E. Goldgar , Torben A. Kruse , Edenir Inêz Palmero , Sue Kyung Park , Diana Torres , Elizabeth Jansen van Rensburg , Lesley Mcguffog , Michael Parsons , Goska Leslie , Cora Aalfs , Julio Abugattas , Julian Adlard , Simona Agata , Kristiina Aittomäki , Lesley Andrews , Irene Andrulis , Adalgeir Arason , Norbert Arnold , Banu Arun , Ella Asseryanis , Leo Auerbach , Jacopo Azzollini , Judith Balmaña , Monica Barile , Rosa Barkardottir , Daniel Barrowdale , Javier Benitez , Andreas Berger , Raanan Berger , Amie Blanco , Kathleen Blazer , Marinus Blok , Valérie Bonadona (1) , Bernardo Bonanni , Angela Bradbury , Carole Brewer , Bruno Buecher (2) , Saundra Buys , Trinidad Caldés , Almuth Caliebe , Maria Adelaide Caligo , Ian Campbell , Sandrine Caputo (2) , Jocelyne Chiquette , Wendy Chung , Kathleen Claes , J Margriet Collée , Jackie Cook , Rosemarie Davidson , Miguel de La Hoya , Kim de Leeneer , Antoine de Pauw (2) , Capucine Delnatte (3) , Orland Diez , Yuan Chun Ding , Nina Ditsch , Susan Domchek , Cecilia Dorfling , Carolina Velazquez , Bernd Dworniczak , Jacqueline Eason , Douglas F. Easton , Ros Eeles , Hans Ehrencrona , Bent Ejlertsen , Christoph Engel , Stefanie Engert , D Gareth Evans , Laurence Faivre (4, 5) , Lídia Feliubadaló , Sandra Fert Ferrer (6) , Lenka Foretova , Jeffrey Fowler , Debra Frost , Henrique Galvão , Patricia Ganz , Judy Garber , Marion Gauthier-Villars (2) , Andrea Gehrig , Anne-Marie Gerdes , Paul Gesta (7) , Giuseppe Giannini , Sophie Giraud (1) , Gord Glendon , Andrew Godwin , Mark Greene , Jacek Gronwald , Angelica Gutierrez-Barrera , Eric Hahnen , Jan Hauke , Alex Henderson , Julia Hentschel , Frans Hogervorst , Ellen Honisch , Evgeny Imyanitov , Claudine Isaacs , Louise Izatt , Angel Izquierdo , Anna Jakubowska , Paul James , Ramunas Janavicius , Uffe Birk Jensen , Esther John , Joseph Vijai , Katarzyna Kaczmarek , Beth Karlan , Karin Kast , Sung-Won Kim , Irene Konstantopoulou , Jacob Korach , Yael Laitman , Adriana Lasa , Christine Lasset (1) , Conxi Lazaro , Annette Lee , Min Hyuk Lee , Jenny Lester , Fabienne Lesueur (8) , Annelie Liljegren , Noralane Lindor , Michel Longy (9) , Jennifer Loud , Karen Lu , Jan Lubinski , Eva Machackova , Siranoush Manoukian , Veronique Mari (10) , Cristina Martínez-Bouzas , Zoltan Matrai , Noura Mebirouk (8) , Hanne Meijers-Heijboer , Alfons Meindl , Arjen Mensenkamp , Ugnius Mickys , Austin Miller , Marco Montagna , Kirsten Moysich , Anna Marie Mulligan , Jacob Musinsky , Susan Neuhausen , Heli Nevanlinna , Joanne Ngeow , Huu Phuc Nguyen , Dieter Niederacher , Henriette Roed Nielsen , Finn Cilius Nielsen , Robert Nussbaum , Kenneth Offit , Anna Öfverholm , Kai-Ren Ong , Ana Osorio , Laura Papi , Janos Papp , Barbara Pasini , Inge Søkilde Pedersen , Ana Peixoto , Nina Peruga , Paolo Peterlongo , Esther Pohl , Nisha Pradhan , Karolina Prajzendanc , Fabienne Prieur (11) , Pascal Pujol (12, 13) , Paolo Radice , Susan Ramus , Johanna Rantala , Muhammad Usman Rashid , Kerstin Rhiem , Mark Robson , Gustavo Rodriguez , Mark Rogers , Vilius Rudaitis , Ane Schmidt , Rita Katharina Schmutzler , Leigha Senter , Payal Shah , Priyanka Sharma , Lucy Side , Jacques Simard , Christian Singer , Anne-Bine Skytte , Thomas Slavin , Katie Snape , Hagay Sobol (14) , Melissa Southey (14) , Linda Steele , Doris Steinemann , Grzegorz Sukiennicki , Christian Sutter , Csilla Szabo , Yen Tan , Manuel R Teixeira , Mary Beth Terry , Alex Teulé , Abigail Thomas , Darcy Thull , Marc Tischkowitz , Silvia Tognazzo , Amanda Ewart Toland , Sabine Topka , Alison Trainer , Nadine Tung , Christi van Asperen , Annemieke van Der Hout , Lizet van Der Kolk , Rob van Der Luijt , Mattias van Heetvelde , Liliana Varesco , Raymonda Varon-Mateeva , Ana Vega , Cynthia Villarreal-Garza , Anna von Wachenfeldt , Lisa Walker , Shan Wang-Gohrke , Barbara Wappenschmidt , Bernhard Weber , Drakoulis Yannoukakos , Sook-Yee Yoon , Cristina Zanzottera , Jamal Zidan , Kristin Zorn , Christina Hutten Selkirk , Peter Hulick , Georgia Chenevix-Trench , Amanda Spurdle , Antonis C. Antoniou , Katherine Nathanson

1 Centre Léon Bérard [Lyon]
2 Institut Curie [Paris]
3 CRLCC René Gauducheau
4 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
5 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
6 Centre Hospitalier Métropole Savoie [Chambéry]
7 CH Georges Renon Niort - Centre Hospitalier Georges Renon [Niort]
8 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
9 Plateforme de génétique moléculaire des cancers d'Aquitaine
10 UNICANCER/CAL - Centre de Lutte contre le Cancer Antoine Lacassagne [Nice]
11 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
12 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
13 UM - Université de Montpellier
14 IPC - Institut Paoli-Calmettes

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.

Keywords: BRCA1; BRCA2; breast cancer; ethnicity; geography; mutation; ovarian cancer

Domains: Human genetics

Timothy Rebbeck, Tara Friebel, Eitan Friedman, Ute Hamann, Dezheng Huo, et al.. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Human Mutation, 2018, 39 (5), pp.593-620. ⟨10.1002/humu.23406⟩. ⟨hal-02351570⟩