A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas U. Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton‐Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heiko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Åke Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang‐Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen Claes, Christine L. Clarke, GEMO Study Collaborators, Ophélie Bertrand, Sandrine M. Caputo, Anaïs Dupré, Marine Le Mentec, Muriel Belotti, Anne-Marie Birot, Bruno Buecher, Emmanuelle Fourme, Marion Gauthier-Villars, Lisa Golmard, Claude Houdayer, Virginie Moncoutier, Antoine de Pauw, Claire Saule, Olga Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Mélanie Léone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud, Olivier Caron, Marine Guillaud-Bataille, Brigitte Bressac–de Paillerets, Yves- Jean Bignon, Nancy Uhrhammer, Christine Lasset, Valérie Bonadona, Pascaline Berthet, Dominique Vaur, Laurent Castéra, Tetsuro Noguchi, Cornel Popovici, Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, Catherine Noguès, Isabelle Coupier, Pascal Pujol, Aurélie Dumont, Françoise Révillion, Claude Adenis, Danièle Muller, Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy, Christine Toulas, Rosine Guimbaud
Abstract
Abstract Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10 −8 , at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD , SP11 and EIF1 , genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.