Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

Abstract

Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.

Figure 1

Summary of the study design. Stages 1 and 2 are as reported in Easton et al.. Stages 3 and 4, below the dotted line, are the stages conducted in this follow-up study.

Figure 2

Forest plots of the per-allele OR by study for rs4973768 (left) and rs6504950 (right). Squares represent the estimated OR for each study. Lines indicate the 95% confidence interval. Diamonds represent the OR estimates and confidence limits for the subgroups indicated.

Figure 3

Maps of associated regions on 3p24 and 17q23.2. (a) HapMap CEU–derived ~ 600-kb LD block around the 3p loci illustrating all the common SNPs (MAF 0.05). Extent of block delimited by dotted lines. Squares on the LD block indicate the correlation (r²) between SNP genotypes on a greyscale (darker squares = higher correlations). Approximate size and transcripts of NEK10 (chromosome positions 2712398–27307988) and SLC4A7 (chromosome positions 27389218–27473249) inferred from the NCBI reference assembly (solid arrow) and Ensembl (dashed arrow) are indicated. Genotyped tag SNPs are marked by circles: black filled circles show SNPs significantly (P < 0.05) associated with breast cancer in the SEARCH study; black-outline-only circles show tag SNPs not associated with disease. The most strongly associated tag SNPs, as discussed in the text, are marked by stars (1, rs1357245; 2, rs4973768; 3, rs2307032). (b) HapMap CEU–derived ~ 300-kb LD block on 17q tagged rs6504950 (marked by star). Extent of block delimited by dotted lines. The approximate size and transcripts associated with the three known nearby genes COX11, TOM1L1 and STXBP4 as inferred by NCBI are indicated.