A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population

Abstract

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10⁻⁹ to P(trend) = 3.9 × 10⁻⁷), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 × 10⁻⁷) to P(trend) = 8 × 10⁻⁵; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 × 10⁻⁷

Figure 1

Forest plots of the associations by country of residence of BRCA1 mutation carriers in the combined stage 1 and stage 2 samples. (a,b) Squares indicate the country specific per-allele HR estimates for SNPs rs8170, rs4808611 (a) and rs8100241, rs2363956 (b). The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines indicate 95% CIs.

Figure 2

Above, results of the kinship-adjusted score test statistic (1 d.f.) by position (kb) in stage 1 and 2 samples combined for genotyped and imputed SNPs in the associated region (chromosome 19, positions 17,100–17,400 kb). Genotyped SNPs in stages 1 or 2 are shown in red and imputed SNPs are shown in black. The horizontal dotted line indicates the P values for the strongest association among genotyped SNPs (rs8170). At middle, the linkage disequilibrium (LD) blocks around the top five associated SNPs (chromosome 19, positions 17,150–17,350 kb) in the combined analysis of stage 1 and stage 2 samples based on the 1000 Genomes Project data for the samples of European ancestry. Squares in the LD blocks indicate pairwise correlations between the SNPs (r²) by grayscale (darker symbols indicate correlations closer to 1). Below, details of the region containing the most significantly associated genotyped and imputed SNPs (chromosome 19, positions 17,210–17,268 kb). Location of genotyped SNPs shown by numbers 1–5 and the eight most significantly associated imputed SNPs are shown in letters A–H (P = 9.0 × 10⁻¹² to P = 1.0 × 10⁻¹¹).