Association of polymorphisms of genes involved in the androgen metabolism and signaling pathways with familial prostate cancer risk in a Japanese population

1318 Androgen plays a central role in normal and malignant growth and function of prostate glands, and differences in androgen metabolism and signaling pathways might have influence on carcinogenesis of prostate cancer. Genetic polymorphisms of genes related with these pathways have attracted attention of researchers in relation to genetic susceptibility to prostate cancer. In the present study, we studied the association of familial prostate cancer risk with genetic polymorphisms involved in the androgen metabolism and signaling pathways. One hundred and two patients with prostate cancer with family history and 117 healthy age- and residence-matched male controls were enrolled. Genotypes of CAG repeat length of androgen receptor (AR), CYP17, 5α-reductase type II (SRD5A2), UDG-glucuronosyltransferase (UGT) 2B15, PSA promoter genes were analyzed. For single polymorphisms, the presence of Y alleles showed a significantly lower risk of prostate cancer in comparison with the D/D genotype in UGT2B15 (odds ratio [OR]=0.41, 95% confidence interval [CI]=1.40-4.28, p=0.0015), and the presence of A2 alleles showed a weak tendency to decrease prostate cancer risk in comparison with the A1/A1 genotype in CYP17 (OR=0.69, 95%CI=0.39-1.23, p=0.21). No significant associations were found in AR CAG repeat length, SRD5A and PSA promoter genotype with risk. Stratification of cases according to clinical stage and pathological grade showed that the A2/A2 genotype was significantly associated with localized stage cancer in comparison with metastatic stage cancer (OR=5.18, 95% CI = 1.49-17.95, p=0.007). Combination of genotypes of UGT2B15 and CYP17 could select higher risk subjects even in subjects with low risk UGT2B15 genotypes, i.e., Y/Y + D/Y genotypes (OR=1.97, 95%CI=0.92-4.22, p=0.079). Genetic polymorphisms of genes involved in androgen metabolism and signaling were significantly associated with familial prostate cancer risk. Single nucleotide polymorphisms of low penetrance genes could be targets to understand the genetic susceptibility to familial prostate cancer.