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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Coignard, Juliette 
Lush, Michael 
Beesley, Jonathan 

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.

Description

Keywords

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

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

12

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research Uk (None)
Cancer Research UK (16563)
Cancer Research Uk (None)
Cancer Research UK (20861)
Medical Research Council (G1000143)
National Cancer Institute (U19CA148537)
National Cancer Institute (U19CA148065)
Cancer Research UK (10710)
Cancer Research UK (11990)
Cancer Research UK (12014)
Cancer Research UK (10118)
National Cancer Institute (R01CA128978)
European Commission Horizon 2020 (H2020) Societal Challenges (634935)
European Commission Horizon 2020 (H2020) Societal Challenges (633784)
Medical Research Council (G0401527)
Medical Research Council (MR/N003284/1)
Medical Research Council (G0401527/1)
Cancer Research UK (23382)