Relationship between glutathione S-transferase M1, P1 and T1 polymorphismsand early onset prostate cancer

There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-ind ividual differences in cancer susceptibility may be mediated in part throug h polymorphic variability in the bioactivation and detoxification of carcin ogens. The GSTs have been consistently implicated as cancer susceptibility genes in this context. The GST supergene family includes several loci with well characterized polymorphisms. Approximately 50% of the Caucasian popula tion are homozygous for deletions in GSTM1 and approximately 20% are homozy gous for deletions in GSTT1, resulting in conjugation deficiency of mutagen ic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an lie to Val substitution which consequently alters the enzymatic activity of the protein and this has been suggested as a putative high-risk genotype in various cancers. We investigated the relationship be tween GST polymorphisms and young onset prostate cancer in a case-control s tudy. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate can cer patients and for 280 geographically matched control subjects, We found no significant difference in the frequency of GSTM1 or GSTT1 null genotypes between cases and controls. GSTP1 genotype was, however, significantly ass ociated with prostate cancer risk: the Ile/Ile homozygotes had the lowest r isk and there was a trend in increasing the risk with the number of 105 Val alleles: Ile/Val odds ratio (OR)= 1.30 (95% FCI 0.99-1.69), Val/Val OR = 1 .80 (95% FCI 1.11-2.91); P-(trend)= 0.026, These results suggest that the G STP1 polymorphism may be a risk factor for developing young onset prostate cancer. We also found that carrying more than one putative high-risk allele in the carcinogen metabolizing GST family was associated with an elevated risk for early onset prostate cancer (OR 2.28, 95% FCI 1.22-5.04, P-trend = 0.017). Pharmacogenetics 11:325-330 (C) 2001 Lippincott Williams & Wilkins .