Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
A partir de données portant sur 43 160 cas et 42 600 témoins d'origine européenne, ainsi que 5 795 cas et 6 624 témoins d'origine asiatique, cette étude identifie, sur la région chromosomique 9q31.2, deux nouveaux loci de susceptibilité au cancer du sein
We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43,160 cases and 42,600 controls of European ancestry ascertained from 52 studies and a further 5,795 cases and 6,624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (OR=0.90 [0.88-0.92]; P-value=1.58 x 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans approximately 14.5 Kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR=1.12 [1.08-1.17]; P-value=7.89 x 10−09) and rs13294895 (OR=1.09 [1.06-1.12]; P-value=2.97 x 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR=1.12 [1.06-1.18]; P-value=2.77 x 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
http://hmg.oxfordjournals.org/content/early/2015/02/04/hmg.ddv035.abstract