Identification of genetic polymorphisms at the glutathione S- transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer

Abstract

A versus G. This results in a single amino acid difference, EH4 2XU, UK valine versus isoleucine at codon 105 (Figure This residue 4 To whom correspondence should be addressed lies in close proximity to the hydrophobic binding site for electrophilic substrates In order to establish whether these base pair (AG) substitution at nucleotide 313 of the sequences represent alleles at the GSTP1 locus, we designed GSTP1 cDNA. This results in an amino acid substitution a PCR assay to rapidly and simply detect their presence in the which alters the function of the enzyme. In this study, a population. Since GSTP1 is a major enzyme involved in the novel PCR assay has been developed which demonstrates inactivation of cigarette smoke carcinogens such as benzo[a]that these two variant cDNAs represent distinct GSTP1 pyrene diol epoxide and also other toxic cigarette smoke alleles (GSTP1a and GSTP1b). In a study of individuals constituents such as acrolein (1), we were interested to deterwith different forms of cancer, the GSTP1b allele is found mine whether this polymorphism was related to diseases to be strongly associated with bladder cancer and testicular associated with cigarette smoking such as certain types of cancer. In controls 6.5% of individuals were homozygous cancer and chronic obstructive pulmonary disease (COPD*). for the GSTP1b allele. In bladder cancer cases, this rose to 19.7% [n 71, odds ratio 3.6 (1.4-9.2), P 0.006] and in testicular cancer to 18.7% [n 155, odds ratio 3.3 (1.5-Materials and methods 7.7), P 0.002]. In addition, in prostate cancer a highly Patient materials significant decrease in the frequency of the GSTP1a homo-Populations analysed for GSTP1 genotype were 155 control individuals from zygotes was observed [control 51.0% versus 27.8% cancer the Edinburgh area. These random samples were obtained from the Clinical cases, n 36, odds ratio 0.4 (0.02-3.3), P 0.008]. Biochemistry Department at Edinburgh Royal Infirmary; they were all Caucasi-Increases in the frequency of GSTP1b homozygotes was ans. Other samples tested were 79 COPD cases; 155 lung cancer cases [mean age 67.2 years (49-87 years), 97% smokers or ex-smokers, 69% males]; 71 also observed in lung cancer and chronic obstructive bladder cancer cases [mean age 72.2 years (54-91 years), 86% smokers or pulmonary disease. However, these were not statistically ex-smokers, 68% males]; 90 teratoma cases [mean age 40.5 years (22-56 significant. No change in breast or colon cancer allele years), 70% smokers or ex-smokers]; 65 seminoma cases [mean age 45.6 frequencies was observed. years (30-64 years), 50% smokers or ex-smokers]; 36 prostatic cancer cases [mean age 70.4 years (62-88 years), 90% smokers or ex-smokers]; 62 breast cancer cases [mean age 60.3 years (37-82 years), 60% smokers or ex-smokers] and 100 colon cancer cases were studied. All samples from cancer patients