Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The glutathione S-transferases (GSTs) are involved in the metabolism of numerous potential prostate carcinogens. Common homozygous germ-line deletions exist in the genes that encode GST-mu (GSTM1) and GST-theta (GSTT1) and preclude enzyme expression. To evaluate whether GSTM1 and/or GSTT1 contribute to prostate cancer (CaP) etiology, we studied 237 incident CaP cases and 239 age- and race-matched controls. The probability of having CaP was increased in men who had nondeleted (functional) genotypes at GSTT1 (odds ratio, 1.83; 95% confidence interval, 1.19-2.80) but not GSTM1 (odds ratio, 1.07; 95% confidence interval, 0.74-1.55). No interaction of these genes in CaP etiology was observed. GST-theta is highly expressed in the prostate and can produce genotoxic effects upon exposure to specific carcinogens. These results suggest that GSTT1 is associated with CaP risk.
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PMID:Glutathione S-transferase-mu (GSTM1) and -theta (GSTT1) genotypes in the etiology of prostate cancer. 1020 29

Glutathione S-transferases are enzymes involved in the metabolism of carcinogens and in the defence against reactive oxygen species. Genetic polymorphisms have been detected in glutathione S-transferases M1, T1 and P1, and some of these polymorphisms have been associated with an increased risk of cancer. In a case-control study (153 cases and 288 controls) the effect of these genetic polymorphisms on the risk of prostate cancer was investigated. Homozygote deletion of either GSTM1 or GSTT1 was not associated with a statistically significant increased risk, odds ratio (OR) 1.3; 95% confidence intervals (CI) 0.9-1.9 and 1.3; 0.8-2.2, respectively. Deletion of both GSTM1 and GSTT1 gave a near-significant increased risk (OR 1.7; 95% CI 0.9-3.4). Two allelic variants of GSTP1 (codon 105) have been reported. This polymorphism was not linked to an increased risk (OR 0.8; 95% CI 0.5-1.1). Smokers that lack either GSTM1 or GSTT1 activity had a slightly higher risk of prostatic cancer than smokers expressing the genes, OR 1.4 (95% CI 0.6-3.3) and 1.6 (0.6-3.9), respectively. Our results show that differences in enzymes involved in the metabolism of carcinogens slightly modify prostate cancer risk, especially in people exposed to carcinogens that are detoxified by these enzymes.
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PMID:Glutathione S-transferases as risk factors in prostate cancer. 1064 42

It has been reported that individuals who express GSTT1, the gene coding for the theta class of the glutathione S-transferases (GSTs), have an elevated risk of prostate cancer (CaP). This result is supported by studies that show glutathione conjugation of some xenobiotics by the GSTs can produce mutagenic intermediates. However, the potential role of environmental factors in modifying the risk of CaP conferred by GSTT1 is not known. We investigated whether there was an interaction between smoking and the non-deleted genotypes of the mu (GSTM1) and theta (GSTT1) GST genes using a clinic-based study of 276 CaP cases and 499 controls. We observed no main effect of smoking (odds ratio, 0.95; confidence interval, 0.69-1.29) or GSTM1 (odds ratio, 1.00; confidence interval, 0.73-1.36) with CaP, but did observe a statistically significant main effect of GSTT1 with CaP (odds ratio, 1.61; confidence interval, 1.14-2.28) as reported previously. No interaction between smoking and GSTM1 was observed. A significant increase in the probability of having CaP was observed in men who were both smokers and carried a non-deleted GSTT1 genotype compared with men who had neither or only one of these risk factors (P = 0.049). Approximately 30.9% of CaP cases in this study could be attributed to the smoking x GSTT1 interaction. Whereas the mechanism of this interaction is not known, it is plausible that the metabolism of carcinogenic intermediates or the response to chronic inflammation associated with smoking may be modulated by the GSTT1 genotype and may modify CaP risk.
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PMID:The glutathione S-transferase-mu and -theta genotypes in the etiology of prostate cancer: genotype-environment interactions with smoking. 1114 18

Associations between genetic polymorphisms of CYP1A1, CYP1A2, CYP2E1, GSTM1 and GSTT1 and prostate cancer (PCa) were analyzed in a case-control study of 315 individuals. The frequency of valine (Val)/valine (Val) genotypes for CYP1A1 was 11.3% in cases compared with 5.5% in controls, this polymorphism thus being associated with a significantly increased risk of PCa (odds ratio=2.4, 95% confidence interval (CI)=1.01-5.57). No links were detected between PCa and polymorphisms in other enzymes. However, the combination of CYP1A1 (Ile/Val and/or Val/Val) polymorphisms with the GSTM1 null type resulted in an OR of 2.2 (CI=1.10-4.57, 1.12-4.20, respectively). This study suggests that the CYP1A1 polymorphism and its combination with GSTM1 may be associated with PCa susceptibility in the Japanese population.
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PMID:Genetic polymorphisms in cytochrome P450 (CYP) 1A1, CYP1A2, CYP2E1, glutathione S-transferase (GST) M1 and GSTT1 and susceptibility to prostate cancer in the Japanese population. 1127 66

Several polymorphic glutathione-S-transferase (GST) enzymes are involved in the metabolism of a number of potential prostate carcinogens and are thought to engage in the transport of steroid hormones. A case-control study was conducted to determine the association of the GSTP1, GSTM1 and GSTT1 polymorphisms and prostate-cancer risk. The study population consisted of 166 patients with previously untreated, histologically proven prostate cancer and 166 age-matched control patients with benign prostatic hyperplasia (BPH), all of them Caucasians. In the GSTP1 gene, 2 polymorphic alleles, GSTP1*B and GSTP1*C, have been described in addition to the wild-type allele, GSTP1*A. Both polymorphic GSTP1 alleles have an A-to-G transition in exon 5, causing an isoleucine-to-valine change. The GSTP1*C allele has an additional transition from C to T. For GSTM1 as well as GSTT1, the polymorphic allele is a deletion of the gene. The proportion of individuals homozygous for the GSTP1 variant alleles (GSTP1*B/*B, GSTP1*B/*C and GSTP1*C/*C) was significantly lower in prostate-cancer patients (4.8%) than in BPH controls (14.5%), and the odds ratio (OR) was 0.24 [95% confidence interval (CI) = 0.09-0.61). The heterozygous genotypes (GSTP1*A/*B and GSTP1*A/*C) were also lower in the cancer group, though this was not significant. On the contrary, no significant effect on prostate-cancer risk was detectable for either GSTM1 (OR = 0.86, 95% CI = 0.55-1.36) or GSTT1 (OR = 0.78, 95% CI = 0.43-1.42). Of the polymorphic GSTs, GSTP1 is the most interesting candidate as a biomarker for prostate-cancer risk as we found a 76% reduced risk in men homozygous for the polymorphic GSTP1 alleles compared to those with wild-type GSTP1.
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PMID:Polymorphisms of glutathione-S-transferase genes (GSTP1, GSTM1 and GSTT1) and prostate-cancer risk. 1130 47

There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. 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 population are homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1, resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an Ile 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 between GST polymorphisms and young onset prostate cancer in a case-control study. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate cancer 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 associated with prostate cancer risk: the Ile/Ile homozygotes had the lowest risk 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); Ptrend = 0.026. These results suggest that the GSTP1 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 2.48, 95% FCI 1.22-5.04, Ptrend = 0.017).
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PMID:Relationship between glutathione S-transferase M1, P1 and T1 polymorphisms and early onset prostate cancer. 1143 10

Molecular epidemiological association studies use valuable biosamples and incur costs. Statistical methods for early genotyping termination may conserve biosamples and costs. Group sequential methods (GSM) allow early termination of studies on the basis of interim comparisons. Simulation studies evaluated the application of GSM using data from a case-control study of GST genotypes and prostate cancer. Group sequential boundaries (GSB) were defined in the EAST-2000 software and were evaluated for study termination when early evidence suggested that the null hypothesis of no association between genotype and disease was unlikely to be rejected. Early termination of GSTM1 genotyping, which demonstrated no association with prostate cancer, occurred in >90% of the simulated studies. On average, 36.4% of biosamples were saved from unnecessary genotyping. In contrast, for GSTT1, which demonstrated a positive association, inappropriate termination occurred in only 6.6%. GSM may provide significant cost and sample savings in molecular epidemiology studies.
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PMID:Group sequential methods and sample size savings in biomarker-disease association studies. 1266 57

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 chi(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.
Prostate Cancer Prostatic Dis 2002
PMID:Polymorphisms of GSTP1 and related genes and prostate cancer risk. 1519 26

Cruciferous vegetables contain anticarcinogenic isothiocyanates (ITCs), particularly the potent sulforaphane, which may decrease risk of prostate cancer through induction of phase II enzymes, including glutathione S-transferases (GSTs). We evaluated this hypothesis in a population-based, case-control study of prostate cancer, including 428 men with incident prostate cancer and 537 community controls. An in-person interview included an extensive food-frequency questionnaire. Genotyping for deletions in GSTM1 and GSTT1 was performed in a subset of men who provided blood. Intakes of cruciferous vegetables and of broccoli, the greatest source of sulforaphane, were associated with decreased prostate cancer risk at all levels above the lowest consumers [adjusted 4th quartile odds ratio (OR)=0.58; 95% confidence interval (CI)=0.38, 0.89, and 0.72 (95% CI=0.49, 1.06)], respectively. In relation to genotypes, there was a nonsignificant increase in risk with the GSTT1 null genotype (OR=1.51; 95% CI=0.98, 2.31) but no effects of GSTM1 genotype. However, men with GSTM1-present genotype and high broccoli intake had the greatest reduction in risk (OR=0.49; 95% CI=0.27, 0.89). Our findings provide evidence that two or more servings per month of cruciferous vegetables may reduce risk of prostate cancer, especially among men with GSTM1-present alleles, and are consistent with a role of dietary ITCs as chemopreventive agents against prostate cancer.
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PMID:Cruciferous vegetables, genetic polymorphisms in glutathione S-transferases M1 and T1, and prostate cancer risk. 1562 68

The glutathione S-transferase (GST) gene superfamily encodes for enzymes involved in conjugation of electrophilic compounds to glutathione. Several polymorphisms in the GST genes have been implicated as risk factors for prostate cancer. We did a meta-analysis of 11 studies with GSTM1 genotyping (2,063 prostate cancer cases and 2,625 controls), 10 studies with GSTT1 genotyping (1,965 cases and 2,554 controls), and 12 studies with GSTP1 genotyping (2,528 cases and 3,076 controls). The random effects odds ratio was 1.08 [95% confidence interval (95% CI), 0.93-1.25, no significant between-study heterogeneity] for the GSTM1 null versus nondeleted genotype and 0.90 (95% CI, 0.73-1.12; P = 0.03 for heterogeneity) for the GSTT1 null versus nondeleted genotype. Overall, the random effects odds ratio was 1.05 (95% CI, 0.90-1.21; P < 0.01 for heterogeneity) for the GSTP1-Val versus GSTP1-Ile allele. For all three polymorphisms, there was a trend for the presence of an association in the earliest published studies, but this did not seem to be validated in subsequent research. For GSTT1, larger studies gave different results than smaller ones. The meta-analysis shows that these three polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.
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PMID:Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis. 1566 93


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