Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC
Introduction
A single nucleotide polymorphism (SNP) in the caspase-8 gene, (CASP8 D302H), has been reported to be involved in susceptibility to breast and pancreatic cancer, melanoma and glioma, but not colorectal or ovarian cancer. We previously have used a tagging-SNP approach to test the hypothesis that this SNP, or other variants in CASP8, were associated with prostate cancer, in 1009 cases, 987 men with normal serum prostate specific antigen (PSA) levels and 961 men with low serum PSA (<0.5ng/ml). These subjects were drawn from those participating in the UK ProtecT (Prostate Testing for Cancer and Treatment) trial. Of the 15 tagging SNPs in caspase-8 that were genotyped, 7 showed some evidence of association with prostate cancer (P<0.05). The aim of the present study was to attempt to replicate these results in an independent set of case and control subjects.
Methods
A further independent sample of men from the ProtecT trial formed the replication cohort for this study. Blood DNA samples were available for 1262 men with prostate cancer, 1258 men with normal serum PSA, and 609 men with low serum PSA. SNP genotyping was carried out by 5-prime nuclease PCR (TaqmanTM, Applied Biosystems). The association with prostate cancer was tested using logistic regression, controlling for sample set.
Results
Two SNPs with duplicate concordance rates of less than 98% were not included in the analysis. Genotype call rates for the remaining 5 SNPs were all greater than 95%, and genotype frequencies in control subjects were consistent with those expected under Hardy-Weinberg equilibrium. None of the 5 SNPs yielded significant evidence of association in the replication cohort, although some odds ratios were consistent between the two data sets. We combined the data from the test and replication cohorts to evaluate the overall evidence for association. The rare alleles of rs3769826 and rs6723097 conferred a reduced risk of prostate cancer with per-allele odds ratios (95% confidence interval) [OR(95%CI)] of 0.90 (0.82-0.98) and 0.88 (0.80-0.96), and P=0.013 and P=0.004 respectively. In addition, the deletion allele of the promoter indel rs3834129 conferred an increased risk of prostate cancer, with OR (95%CI) of 1.15 (1.05-1.27), P=0.003. While these results await further replication, it is interesting to note that the rare alleles of rs3769826 and rs6723097 are carried on European haplotypes that are associated with increased risk of breast cancer, suggesting the possibility of a different mode of action of caspase-8 in the two tumour types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2843.