Abstract
Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Highlights
Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (Po5 Â 10 À 8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk
Associations with ER-negative breast cancer. Genotype data for this meta-analysis were obtained from three sources: (1) 11 breast cancer genome-wide association studies (GWAS) included 5,139 ER-negative breast cancer cases and 14,352 controls (Supplementary Table 1); (2) The Breast Cancer Association Consortium (BCAC) included 7,333 ER-negative breast cancer cases and 42,468 study-matched controls genotyped
Imputation was performed using the 1000 Genomes project as a reference[20,27], and a meta-analysis was performed based on 10,909,381 common single-nucleotide polymorphisms (SNPs) that passed quality control (Supplementary Table 1)
Summary
Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (Po5 Â 10 À 8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. The alleles associated with ER-negative breast cancer[3,17] at these loci have been associated with breast cancer risk in BRCA1 mutation carriers[21,22], consistent with the finding that the majority of breast tumours arising in BRCA1 mutation carriers show low/absent expression of ER23–25. These observations suggest that a meta-analysis of results from ER-negative breast cancer and BRCA1 breast cancer association studies could identify additional ER-negative susceptibility loci that were not found previously because of limited sample size. We carried out a meta-analysis of breast cancer GWAS studies and found four new loci associated with developing ER-negative breast cancer
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