One approach to improve our understanding of the aetiology of breast cancer is to identify the genes involved in inherited susceptibility. These range from the rare high-penetrance mutations of the BRCA1 and BRCA2 genes to common low-penetrance variants, which are just beginning to be identified by means of whole-genome and candidate gene association studies. Owing to their small effect, these common variants are difficult to identify, requiring studies with large sample sizes. The Breast Cancer Association Consortium recently identified a single nucleotide polymorphism (SNP) in the CASP8 gene that is associated with a reduction in risk of breast cancer (rs1045485; D302H; Ptrend = 1.1 × 10-7) in a large multicentre cohort .
To further investigate the association between the CASP8 gene and breast cancer, we genotyped 15 haplotype-tagging SNPs across a 60 kb region spanning CASP8 in 1,200 cases and 1,200 controls from Sheffield. Two further SNPs demonstrated a significant association with breast cancer; rs6435074 (Ptrend = 0.042) and rs6723097 (Ptrend = 0.024). These markers were therefore genotyped in two additional case–control cohorts based in Utah and Germany. The rs6723097 SNP displayed the strongest association with odds ratios of 1.15 (95% CI = 1.02 to 1.29) and 1.35 (95% CI = 1.15 to 1.59), for the heterozygous and rare homozygous genotypes respectively, compared with the common homozygous genotype (Ptrend = 0.0002).
At present there is no functional explanation for the observed associations. Therefore it is possible that the associated SNPs are in linkage disequilibrium with other causative variants; haplotype analysis and further sequencing of the region will be needed to identify these.