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 Ahearn, Kristiina Aittomäki, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J Aronson, Banu K ArunAnnelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heiko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E Bojesen, Bernardo Bonanni, Ake 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 B M Claes, Christine L Clarke, J Margriet Collée, Don M Conroy, Kamila Czene, Mary B Daly, GEMO Study Collaborators, EMBRACE Collaborators, HEBON Investigators, Encarna Gomez Garcia, KConFab Investigators

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number1078
Number of pages22
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 17 Feb 2021

Keywords

  • Adult
  • Alleles
  • BRCA1 Protein/genetics
  • BRCA2 Protein/genetics
  • Breast Neoplasms/genetics
  • Female
  • Genetic Predisposition to Disease/genetics
  • Genome-Wide Association Study/methods
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Middle Aged
  • Mutation
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci/genetics
  • Risk Factors

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