Polymorphisms of GSTP1 and related genes and prostate cancer risk

Abstract

Glutathione S-transferase P1 (GSTP1) is markedly downregulated in prostate cancer and prostatic intraepithelial neoplasia compared to normal prostate tissue. Downregulation of GSTP1 may, therefore, be an early event in prostate carcinogenesis. An A?G polymorphism at nucleotide 313 results in an amino acid substitution (Ile105Val) in the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. In a study of 36 prostate cancer patients, Harries et al. reported that the Ile/Ile genotype is associated with a decreased risk of prostate cancer (odds ratio 0.4 (0.17 -0.82)). We sought to confirm this finding and to examine the impact of this polymorphism together with several related polymorphisms implicated as risk factors for carcinogen-associated malignancies. One hundred and seventeen patients with prostate adenocarcinoma and 183 population-based controls were recruited to this case -control study. Genotyping of the GSTP1 (Ile105Val), GSTM1 (null), GSTT1 (null) and CYP1A1 (Ile462Val) genes was performed using polymerase chain reaction (PCR) based techniques on DNA prepared from peripheral blood. A questionnaire was used to collect demographic information from each subject. Cases were significantly older (P < 0.0001) and had significantly greater family history of prostate cancer (P < 0.0001), confirming known risk factors for this disease. By w 2 analysis, none of the genotype distributions varied among cases and controls. Using a logistic regression model to control for known risk factors we were also unable to demonstrate a significant association with prostate cancer for any of the polymorphisms tested. This population fails to identify a relationship between the above polymorphisms and prostate adenocarcinoma.

Relationship among metabolizing genes, smoking and alcohol used as modifier factors on prostate cancer risk: Exploring some gene?gene and gene?environment interactions

“…Murata et al [44,45] ffound increased association with PCa risk in Japanese people Kote-jarai et al [46] found a higher risk of PCa when they evaluated three of the putative high-risk genotypes (GSTM1 and GSTT1 null and GSTP1 val/val), however, this risk was not significantly different when GSTP1 was considered alone, probably indicating that the GSTM1 and GSTT1 combination is not associated with PCa risk. Neither Rebbeck et al [28] nor Beer et al [47] found an association between PCa and these two null genotypes. In contrast, Steinhoff et al [27] reported a significant association with PCa risk when they evaluated the same genotypes.…”

Glutathione S-transferase: differential expression of α, μ, and π isoenzymes in benign prostate, prostatic intraepithelial neoplasia, and prostatic adenocarcinoma

“…A Finnish study showed that prostate cancer risk was increased among smokers with the GSTM1-present (nondeleted genotype [heterozygous or homozygous presence of the gene]) genotype [76]. For the GSTT1 gene deletion polymorphism, which occurs in 16% of the population, the results were inconclusive [68,70,71,73,76,77]. For the GSTP1 (Ile105Val) polymorphism, most studies have shown no association with prostate cancer [68,69,76,[78][79][80][81], although Mao et al [82] reported a significant interaction between the GSTP1 homozygous isoleucine (Ile/Ile) genotype and smoking, with a 4.5-fold increased risk of prostate cancer.…”

“…The association of the GSTM1, GSTT1, and GSTP1 (Ile105Val) genetic variants with prostate cancer risk has yielded inconsistent results. The GSTM1 enzyme is homozygously deleted in 50% of the population, and most studies have reported moderate increased relative risk (20%-30%, statistically insignificant), or no association between prostate cancer and GSTM1-null genotype [67][68][69][70][71][72][73]. Only 1 study reported a strong relative risk (RR = 1.96) of prostate cancer among GSTM1-null patients [74].…”

<b><i>GSTT1</i></b> Null Genotype Is Associated with an Increased Risk of Prostate Cancer in Caucasians: A Meta-Analysis

“…With our search criterion, 87 individual records were found and 16 studies with a total of 11,648 subjects were finally included in this meta-analysis [13,14,15,16,17,27,28,29,30,31,32,33,34,35,36,37]. Table 1 shows the main characteristics of those 16 case-control studies.…”

“…The most common variant of GSTT1 gene is homozygous deletion (null genotype) which has been suggested to be associated with the loss of enzyme activity, and increased vulnerability to cytogenetic damage and oxidative DNA damage [11]. Many studies have investigated the association between GSTT1 null genotype and the risk of PCa, but the impact of GSTT1 null genotype on PCa in Caucasians is still unclear owing to the obvious inconsistency among such studies [13,14,15,16,17]. The present study aimed to quantify the strength of association between GSTT1 null genotype and the risk of PCa in Caucasians.…”