Association of CASP8 D302H Polymorphism With Reduced Risk of Aggressive Prostate Carcinoma

BACKGROUND. Because of the dramatically different clinical course of aggressive and indolent prostate carcinoma (PCa), markers that distinguish between these phenotypes are of critical importance. Apoptosis is an important protective mechanism for unrestrained cellular growth and metastasis. Therefore, dysfunction in this pathway is a key step in cancer progression. As such, genetic variants in apoptosis genes are potential markers of aggressive PCa. Recent work in breast carcinoma has implicated the histidine variant of CASP8 D302H (rs1045485) as a protective risk allele. METHODS. We tested the hypothesis that the H variant was protective for aggressive PCa in a pooled analysis of 796 aggressive cases and 2,060 controls. RESULTS. The H allele was associated with a reduced risk of aggressive PCa (ORper allele = 0.67, 95% CI: 0.54-0.83, P-trend = 0.0003). The results were similar for European-Americans (ORper allele = 0.68; 95% CI: 0.54-0.86) and African-Americans (ORper allele = 0.61; 95% CI: 0.34-1.10). We further determined from the full series of 1,160 cases and 1,166 controls in the Prostate, Lung, Colorectal, Ovarian (PLCO) population that the protective effect of the H allele tended to be limited to high-grade and advanced PCa (all cases ORper allele = 0.94; 95% CI: 0.79-1.11; localized, low-grade disease ORper (allele) = 0.98; 95% CI: 0.79-1.23; and aggressive disease ORper (allele) = 0.73; 95% CI: 0.50-1.07). CONCLUSION. These results suggest that histidine variant of CASP8 D302H is a protective allele for aggressive PCa with potential utility for identification of patients at differential risk for this clinically significant phenotype. Prostate 70: 646-653, 2010. (C) 2009 Wiley-Liss. Inc.