Abstract# 2556: An investigation of the role of the caspase-8 gene in prostate and colon cancer susceptibility using a SNP-tagging approach

Cox, Angela; Lin, Wei-Yu; Elliott, Graeme; Rigas, Sushila; Bishop, D Timothy; Cannon-Albright, Lisa; Cai, Zheng; Camp, Nicola; Neal, David; Donovan, Jenny and Hamdy, Freddie (2009). Abstract# 2556: An investigation of the role of the caspase-8 gene in prostate and colon cancer susceptibility using a SNP-tagging approach. In: Proc Am Assoc Cancer Res; 2009, Abstract nr 2556, AACR.


We showed recently in a large collaborative study that the rare allele of the caspase-8 (CASP8) gene polymorphism, D302H, is associated with a reduced risk of breast cancer (Cox et al 2007). Subsequently the same SNP has been associated with an increased risk of glioma (Bethke et al, 2008). Further studies based on a panel of SNPs that tag the common variation in CASP8 have indicated that CASP8 variants other than D302H may also be important in cancer susceptibility (Shephard et al, submitted). It is not yet known whether CASP8 variation affects susceptibility to other cancers. In order to test the hypothesis that CASP8 is associated with colon or prostate cancer, we have adopted a SNP-tagging approach. Fifteen CASP tagging-SNPs (tSNPs) were selected by principle components analysis based on in-house genotyping data for 33 common SNPs (minor allele frequency >0.05) on 135 healthy individuals. Colon cancer cases and controls were identified from 4 studies, based in Sheffield and Leeds, UK and Utah, (1261 cases and 1723 controls in total). Prostate cancer cases and controls were derived from the UK ProtecT trial, and comprised 1009 cases, and 987 controls with normal serum PSA (<3ng/ml) and 961 with low serum PSA (<0.5ng/ml). Genotyping of genomic DNA samples from all case and control subjects was carried out in 384-well plates by use of the Applied Biosystems SNPlex® multiplex genotyping system. SNPs with call rates less than 95% or duplicate concordance rates of less than 98% were not included in the analysis. Individual SNPs were tested for association with colon or prostate cancer using a logistic regression framework. None of the tSNPs were associated with colon cancer (Ptrend > 0.15). In the prostate cancer cohort, 3 SNPs in CASP8 yielded significant results when cases were compared to low PSA controls; rs3769826, rs3769824 and rs6723097, with odds ratios (95% confidence intervals) [OR (95%CI)] of 0.87 (0.76, 0.99), 0.68 (0.49, 0.94), and 0.87 (0.75, 1.00) respectively, Ptrend = 0.034, 0.021, 0.049 respectively. Consistent results were also obtained for these 3 SNPs when cases were compared to the normal PSA controls, with OR (95% CI) of 0.876 (0.75, 0.98), 0.68 (0.50, 0.93), and 0.83 (0.73, 0.96) and Ptrend = 0.027, 0.015, 0.010, respectively. These data suggest that there may be an association between CASP8 and prostate cancer, but require replication. Therefore an independent replication study, based on 1262 cases, 1258 normal PSA controls and 609 low PSA controls from the ProtecT study is in progress. It is of interest to note that the rare alleles of these 3 SNPs are carried on European haplotypes that are associated with an increased risk of breast cancer rather than a decreased risk as shown here. If these results were replicated, this would point to a different mode of action of caspase-8 in breast and prostate cancer.

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