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

Kconfab Investigators ,Hebon Investigators ,Abctb Investigators

doi:10.1038/s41467-020-20496-3

Kconfab Investigators , Hebon Investigators + Show 1 more

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https://doi.org/10.1038/s41467-020-20496-3

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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.

Highlights

Breast cancer (BC) is the most common cancer in women worldwide[1] and BC family history is one of the most important risk factors for the disease
A total of 60,212 BCAC cases and 7,257 BRCA1 mutation carrier cases were available for the BRCA1 caseonly analyses and 57,725 BCAC cases and 5,097 BRCA2 mutation carrier cases were available for the BRCA2 case-only analyses (Fig. 1)
A total of 45,881 BCAC controls and 5,750 unaffected BRCA1 mutation carriers were available for the BRCA1 controlonly analyses and 43,549 BCAC controls and 4,456 unaffected BRCA2 mutation carriers for the BRCA2 control-only analyses

Summary

Introduction

Breast cancer (BC) is the most common cancer in women worldwide[1] and BC family history is one of the most important risk factors for the disease. More than 50 of the common genetic BC susceptibility variants have been shown to be associated with BC for BRCA1 and BRCA2 mutation carriers[5,6,15,18,20,39,40,41,42,43,44,45,46,47,48] and their joint effects, summarised as polygenic risk scores (PRS), result in large differences in the absolute risks of developing BC for mutation carriers at the extremes of the PRS distribution[49]. 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 in 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 PRS for BRCA1 and BRCA2 mutation carriers

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