Role of androgen metabolism gene PSA and xenobiotic metabolising enzymes GSTs in prostate cancer risk.

Prostate-specific antigen (PSA) gene expression is regulated by androgen receptor (AR) through androgen response elements (AREs) in the promoter region of the PSA gene. A single nucleotide polymorphism with guanine (G) to adenine (A) substitution is identified at position -158 in the ARE of the PSA gene. Previous studies suggest that this polymorphism may be associated with higher PSA levels and increase prostate cancer risk. Detoxification enzymes glutathione-S-transferases (GSTs) may play a role in the formation of prostate cancer. GSTP1 has a polymorphic site at codon 105 (exon 5), where an adenosine-to-guanosine (A-G) transition causes an Ile-to-Val substitution (Ile105Val) and produces a variant enzyme with lower activity and less capability of effective detoxification. The absence of GSTM1 activity is caused by inheritance of two null alleles (alleles that have a deletion of the GSTM1 gene) similarly; individuals with no GSTT1 activity also have inherited null alleles of the GSTT1 gene, which lead to absence of activity of these enzymes. We have investigated the potential functional significance of these polymorphisms and its association with prostate cancer susceptibility in 145 men diagnosed with prostate cancer and 219 healthy control men. PSA and GSTs polymorphisms were determined by poly-merase chain reaction-based methods using DNA from peripheral blood samples. We did not find a significant association between PSA polymorphism at position – 158 and prostate cancer risk. The OR, calculated relative to subjects with the A/A genotype, was for the A/G genotype 0.95 (95% CL 0.56–1.6, and for the G/G genotype 0.62 (95% CL 0.34–1.12), respectively. We observed non-significant association in null alleles of the GSTM1 (OR = 0.92; 95% CI = 0.59-1.42 and GSTT1 (OR = 0.62, 95% CI = 0.35-1.08) with risk of bladder cancer. Prostate cancer risk was moderately increased with the GSTP1(Val/Val) genotype (OR = 1.46; 95% CI 1.46-4.55). Our findings suggest that GSTP1(Val/Val) genotype may affect the risk of prostate cancer and tumor aggressiveness. Further, GSTM1 null, GSTT1 null genotypes did not appear to influence the susceptibility to prostate cancer.

This work was supported by grants UK/264/2006, MVTS Bil/ ČR/SR/UK/06 and AV 4/0013/05.