GSTT1, GSTM1 and GSTP1 genetic polymorphisms and interaction with tobacco, alcohol and occupational exposure in esophageal cancer patients from North India

Glutathione S-transferases(GSTs) are detoxification enzymes that provide critical defense against carcinogens. Our hypothesis was that altered frequencies of GST genotypes and environmental exposures might be associated with increased susceptibility for the development of esophageal cancer. A total of 100 esophageal cancer patients and 137 age and gender matched healthy controls were analyzed for GST polymorphisms. Frequencies of GSTT1 null, GSTM1 null and GSTP1 genotypes did not differ between patients and controls. However, a two-fold risk was observed for GSTM1 null genotype in adenocarcinoma (OR(odds ratio) 2.1; 95% CI(confidence intervals)=0.53-8.6). Further, we used a case only design to study gene-environment interactions in esophageal cancer. In patients with smoking habits, GSTM1 null and GSTP1 ile/ile genotype were at higher risk for esophageal cancer (OR 1.5; 95% CI=0.50-4.4 and OR 1.3; 95% CI=0.40-3.5), respectively. A moderate risk for cancer was observed from alcohol usage along with GSTM1 null(OR 1.3; 95% CI=0.50-3.6) and GSTP1 val/val genotypes(OR 1.2; 95% CI=0.20-5.7). Interaction of GST genotypes with occupational exposure did not affect risk for esophageal cancer. These findings suggest that genetic polymorphisms of GSTT1, GSTM1, and GSTP1 are not associated with higher risk of esophageal cancer. However, interaction of smoking or alcohol with GSTM1 null or GSTP1 ile/ile moderately increases the risk for esophageal cancer in North Indian population.     

Interactions among GSTM1, GSTT1 and GSTP1 polymorphisms, cruciferous vegetable intake and breast cancer risk

Isothiocyanates are anticarcinogenic phytochemicals found in cruciferous vegetables that both induce and are substrates for the gluthatione S-transferases (GSTs). The GSTs are phase II metabolizing enzymes involved in metabolism of various bioactive compounds. Functional polymorphisms in GST genes have been identified and may interact with cruciferous vegetable intake to affect cancer risk. We examined this hypothesis using data from the Long Island Breast Cancer Study Project, a population-based case-control study conducted in Long Island, NY, from 1996 to 1997. Cruciferous vegetable intake in the previous year was assessed via modified Block food frequency questionnaire. DNA was extracted from blood samples (n = 1052 cases and n = 1098 controls) and genotyped for GSTM1 deletion, GSTT1 deletion and GSTP1 Ile105Val using multiplex polymerase chain reaction and Taqman assays. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI). We found an 86% increase in the OR for breast cancer among carriers of the GSTM1 null, GSTT1 null and GSTP 105Ile/Ile genotypes (OR = 1.86, 95% CI = 1.12, 3.08) and a 36% decrease in the OR among carriers of GSTM1 present, GSTT1 null and GSTP1 105Ile/Val + Val/Val genotypes (OR = 0.64, 95% CI = 0.42, 0.97) compared with GSTM1 present, GSTT1 present and GSTP1 105Ile/Ile carriers. We found no joint effects among GST polymorphisms and cruciferous vegetable intake and breast cancer risk. In conclusion, we found associations between specific combinations of three GST gene polymorphisms and breast cancer risk but these did not modify the association between cruciferous vegetable intake and breast cancer. Additional studies are needed to confirm the associations observed.     

Glutathione S-transferases M1, T1, and P1 and breast cancer.

We examined associations for glutathione S-transferases M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) genotypes and breast cancer in the Carolina Breast Cancer Study, a population-based, case-control study in North Carolina. Odds ratios were close to the null value for each GST locus among African-American women (278 cases and 271 controls) and white women (410 cases and 392 controls), as well as pre- and postmenopausal women. For women with a history of breast cancer in one or more first-degree relatives, odds ratios were 2.1 (95% confidence interval, 1.0-4.2) for GSTM1 null and 1.9 (0.8-4.6) for GSTT1 null genotypes. Among women with a family history, age at diagnosis was significantly earlier for those with the GSTM1 null genotype. We did not observe strong evidence for modification of odds ratios for smoking according to GST genotypes. There was no evidence for combined effects of GSTM1, GSTT1, and GSTP1 genotypes, and there were no combined effects for GST genotypes and the catechol O-methyltransferase genotype. We conclude that GSTM1, GSTT1, and GSTP1 genotypes do not play a strong role in susceptibility to breast cancer. However, the role of GST genotypes in age at onset and risk of breast cancer among women with a family history merits further investigation.     

Genetic polymorphisms in GSTM1, GSTP1, and GSTT1 and the risk for breast cancer: results from the Shanghai Breast Cancer Study and meta-analysis.

PURPOSE: We studied the relation of breast cancer to common deletion mutations in GSTM1 and GSTT1 and the functional Ile(105)Val polymorphism in GSTP1 in a large, population-based case-control study conducted in China and performed a meta-analysis to summarize the literature. EXPERIMENTAL DESIGN: In the case-control study, a total of 1144 breast cancer cases and 1221 community controls were genotyped for GSTM1, GSTP1, and GSTT1 using PCR-based methods. Associations of genotypes and breast cancer were evaluated in logistic regression models. Meta-analysis odds ratios (ORs) were estimated using a fixed effects model. RESULTS: In the case-control study, associations were null for GSTM1 [age-adjusted OR 0.97, 95% confidence interval (CI): 0.82-1.14] and GSTT1 (OR 0.97, 95% CI: 0.83-1.15). A significant increase in risk was observed among homozygotes for the variant Ile(105)Val polymorphism (OR 1.92, 95% CI: 1.21-3.04). No combined effects of GSTM1, GSTP1, and GSTT1 genotypes or interactions with potential effect modifiers were detected. All results were similar in pre- and postmenopausal women and for early versus advanced stage breast cancer. The meta-analysis, based predominantly on Caucasian women, supported null results for the homozygous deletion variant in GSTM1 (summary OR 1.05; combining 19 studies) and GSTT1 (summary OR 1.11; 15 studies). Meta-analysis results for the homozygous GSTP1 variant indicated no overall association (summary OR 1.04; 10 studies), although results varied significantly across studies (P = 0.009). CONCLUSIONS: This large case-control study provides strong support for earlier studies showing no overall association of the GSTM1 and GSTT1 deletion polymorphisms with breast cancer risk. The GSTP1 variant may be relevant to breast cancer risk in Asian populations.     

Meta- and pooled analyses of GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes and risk of head and neck cancer.

Sequence variation in the GSTM1, GSTT1, GSTP1, and CYP1A1 genes may potentially alter susceptibility to head and neck cancers, although evidence from previous studies has not been consistent. To explore these associations, we conducted a meta-analysis of 31 published case-control studies (4635 cases and 5770 controls) and a pooled analysis of original data from nine published and two unpublished case-control studies (2334 cases and 2766 controls). In the meta-analysis, the summary odds ratios (ORs) for head and neck cancer were 1.23 [95% confidence interval (95% CI), 1.06-1.42] for the GSTM1 null genotype, 1.17 (95% CI, 0.98-1.40) for the GSTT1 null genotype, 1.10 (95% CI, 0.92-1.31) for carrying the GSTP1 Val105 allele, and 1.35 (95% CI, 0.95-1.82) for carrying the CYP1A1 Val462 allele. The pooled analysis ORs were 1.32 (95% CI, 1.07-1.62) for the GSTM1 null genotype, 1.25 (95% CI, 1.00-1.57) for the GSTT1 null genotype, 1.15 (95% CI, 0.86-1.53) for carrying the GSTP1 Val105 allele, and 0.98 (95% CI, 0.75-1.29) for carrying the CYP1A1 Val462 allele. Increasing risk of head and neck cancer was observed with inheritance of increasing numbers of modest risk genotypes at the three GST loci (P for trend = 0.04), with the combination of carrying the GSTM1 null, GSTT1 null, and GSTP1 Val105 alleles conferring an OR of 2.06 (95% CI, 1.11-3.81). In conclusion, both the meta- and pooled analysis support modest associations of GSTM1 and GSTT1 genotypes with head and neck cancer risk, and our pooled analysis supports the notion of greater risk when genotypes at multiple GST loci are considered in a multigenic model.     

Marine n-3 fatty acid intake, glutathione S-transferase polymorphisms and breast cancer risk in post-menopausal Chinese women in Singapore

We have previously found marine n-3 fatty acids to be inversely related to post-menopausal breast cancer in Chinese women from Singapore. Post-menopausal women with high [quartiles 2-4 (Q2-Q4)] versus low [quartile 1 (Q1)] intake exhibited a statistically significant reduction in risk of breast cancer after adjustment for potential confounders [relative risk (RR) = 0.66, 95% confidence interval (CI) = 0.50, 0.87]. Experimental studies have demonstrated a direct role for the peroxidation products of marine n-3 fatty acids in breast cancer protection. There is a suggestion that the glutathione S-transferases (GSTs) may be major catalysts in the elimination of these beneficial by-products. Therefore, we hypothesized that individuals possessing the low activity genotypes of GSTM1, GSTT1 and/or GSTP1 (i.e. the GSTM1 null, GSTT1 null and GSTP1 AB/BB genotypes, respectively) may exhibit a stronger marine n-3 fatty acid-breast cancer association than their high activity counterparts. The Singapore Chinese Health Study is a prospective investigation involving 35,298 middle-aged and older women, who were enrolled between April 1993 and December 1998. In this case-control analysis, nested within the Singapore Chinese Health Study, we compared 258 incident breast cancer cases with 670 cohort controls. Overall, breast cancer risk was unrelated to GSTM1 and GSTP1 genotypes. However, the GSTT1 null genotype was associated with a 30% reduced risk of breast cancer [odds ratio (OR) = 0.71, 95% CI = 0.52, 0.96]. Among women with high activity GST genotypes (i.e. GSTM1 positive, GSTT1 positive and GSTP1 AA), no marine n-3 fatty acid-breast cancer relationships were observed in either pre-menopausal or post-menopausal women at baseline. However, post-menopausal women possessing the combined GSTM1 null and GSTP1 AB/BB genotypes showed a statistically significant reduction in risk after adjustment for potential confounders (Q2-Q4 versus Q1, OR = 0.36, 95% CI = 0.14, 0.94). A similar relationship was observed among women with the combined GSTT1 null and GSTP1 AB/BB genotypes (OR = 0.26, 95% CI = 0.08, 0.78).     

Glutathione S-transferase M1 and T1 genetic polymorphisms,alcohol consumption and breast cancer risk

Alcohol consumption has been inconsistently associated with breast cancer risk. Recent studies suggest that genetic polymorphisms of glutathione S-transferases (GSTs) may modify this relation. To determine if breast cancer risk is associated with GSTM1 and GSTT1 genetic polymorphisms, and to evaluate the effect modification between GST genotypes and alcohol consumption in the risk of breast cancer, we conducted a case-control study in the state of Connecticut in the period 1998 and 2001. Cases were histologically confirmed, incident breast cancer patients in New Haven County, CT. Controls were randomly selected from women histologically confirmed to be without breast cancer. The study results show that, while GSTM1 genotypes were not associated with breast cancer risk, GSTT1-null genotype was associated with a significant 90% increased risk for postmenopausal women (OR=1.9, 95% CI 1.2-3.0). Analysis by GST genotypes and alcohol consumption shows that GSTM1A ever-drinking women had a 2.5-fold (OR=2.5, 95% CI 1.1-5.5) increased risk of breast cancer compared to the GSTM1A never-drinkers, and the risk increases with duration and daily amount of alcohol consumption. Postmenopausal women with GSTT1-null genotype, who consumed a lifetime of >250 kg of spirit-equivalents, had an almost seven-fold increased risk (OR=6.8, 95% CI 1.4-33.9), and drinking commencing at younger ages appears to carry a higher risk. An OR of 8.2 (95% CI 1.2-57.4) was observed for those with GSTM1A, and GSTT1-null genotypes who had consumed a lifetime of >250 kg of spirit-equivalents. In conclusion, alcohol consumption may increase breast cancer risk among those who carry susceptible GST genotypes.     

N-acetyltransferase (NAT1, NAT2) and glutathione S-transferase (GSTM1, GSTT1) polymorphisms in breast cancer

To evaluate the potential association between NAT1/NAT2 polymorphisms and breast cancer, a case-control study was conducted in Korean women (254 cases, 301 controls). NAT1 *4/*10 genotype (42%) was the most common NAT1 genotype in this Korean population. The frequencies of slow, intermediate and rapid NAT2 acetylator genotype were 16, 39 and 44% in cases and 16, 42 and 42% in controls. Neither NAT1 rapid (homozygous or heterozygous NAT1 *10) (OR=1.2, 95% CI=0.8-1.9) nor NAT2 rapid acetylator genotype (OR=1.2, 95% CI=0.8-1.7) showed significant association with breast cancer risk. Although the risk of NAT2 rapid acetylator genotype in postmenopausal women (OR=1.4, 95% CI=0.7-2.8) was higher than that in premenopausal women (OR=1.1, 95% CI=0.7-1.7), those were not statistically significant. However, combinations of NAT1, GSTM1 and GSTT1 genotypes showed a significant linear gene-dosage relationship with breast cancer (p for trend=0.04) and those women with NAT2 rapid acetylator and both GSTM1 and GSTT1 null genotypes were at the elevated risk (OR=3.1, 95% CI=1.0-9.1). These results suggest that genetic polymorphisms of NAT1 and NAT2 have no independent effect on breast cancer risk, but they modulate breast cancer risk in the presence of GSTM1 and GSTT1 null genotypes.     

Gluthatione-S-transferase T1-null Genotype Predisposes Adults to Acute Promyelocytic Leukemia; a Case-Control Study

Polymorphisms of glutathione S-transferase (GST) proteins are correlated with elevated risk of many cancersincluding hematologic malignancies. Particularly concerning acute promyelocytic leukemia (APL), the studies onassociation between GSTM1, GSTT1 and GSTP1 and the disease predisposition are scarce and contradictory. Theaim of this study was to examine whether polymorphic variations in GST confer susceptibility to APL. GSTM1and GSTT1 null and GSTP1 Ile105Val alleles were determined using polymerase chain reaction (PCR) andPCR-RFLP, respectively, in 114 APL patients and 99 healthy controls. Frequency of GSTT1 null and GSTM1null genotypes were higher in APL group which it was statistically significant for GSTT1 null (p< 0.01). TheGSTM1 null and GSTT1 null conferred a 1.36-fold (OR= 1.36, 95% CI = 0.79-2.33, p= 0.18) and 2.14-fold (OR=2.14; 95% CI: 1.18-3.92, p= 0.013) increase in risk of APL, respectively, relative to the presence of the GSTM1 orGSTT1 genes. GSTP1 Ile105/Val105 and Val105/Val105 genotypes showed no increase in the risk of APL (OR=0.94; 95% CI: 0.52-1.67 and OR= 1.12; 95% CI: 0.48-2.60, respectively). Our results suggest that GSTT1 nullgenotype may be associated with increased risk of APL.     

Genetic Polymorphisms of Xenobiotic Metabolizing Genes (GSTM1, GSTT1, GSTP1), Gene-Gene Interaction with Association to Lung Cancer Risk in North India; A Case Control Study

Aim: In this case control study involving, 220 human subjects; polymorphisms in xenobiotic metabolizing genes (GST-M1, -T1 and -P1) and their association to lung cancer risk is being analysed among smokers and non-smokers. GSTM1 or GSTT1 gene polymorphism and amino acid changes in GSTP1 have been correlated and may be associated to lung cancer risk. Other factor includes exposure to environmental pollutants and life style choices. We have explored gene-gene and gene-environment interaction in the aetiology of lung cancer risk among north Indian population. Patients and Methods: For the study we have collected 120 lung cancer patient blood samples from Kamala Nehru Memorial Cancer Hospital, Allahabad, Uttar Pradesh and 100 matched controls. DNA was isolated and GST-M1 and - T1 genotyping were assessed by multiplex PCR whereas the GSTP1 polymorphism was analysed using restriction fragment length polymorphism. The risk of lung carcinogenesis was assessed using logistic regression analysis calculating the odd ratio (OR) with 95% confidence interval (CI). Results: The risk of lung carcinogenesis was three fold higher for null GSTT1 (OR=3.045, 95%CI=1.750-5.301, p-value <0.001) genotype; whereas other two types; GSTM1 (OR= 1.342, 95% CI=0.788-2.284, p-value=0.270) and GSTP1 (OR=0.806, 95% CI=0.526-1.236, p-value=0.323) showed no association to lung cancer susceptibility respectively. Smokers diagnosed with lung cancer had more null genotypes for GSTT1 (OR=4.773, 95%CI=1.939-11.751, p<0.001). The ‘at risk’ genotype combination GSTM1 (null) /GSTT1 (null) (OR=1.76, 95%CI; 0.920-3.370, p-value=0.03) showed increased susceptibility to lung cancer risk. The genotype combination of GSTT1 (null)/GSTP1 (Ile/Ile) (p=0.009) was associated with increased lung cancer risk. Conclusion: The results of this study suggest that; GSTT1 null genotype were more susceptible for lung cancer risk and smoking increases the susceptibility for lung cancer several folds among the North Indian population. Gene-gene interaction for null genotypes of GSTM1 and GSTT1 were correlated with higher risk of having lung cancer.     

Glutathione S-transferase M1, T1, and P1 polymorphisms as risk factors for renal cell carcinoma: a case-control study.

Renal cell carcinoma (RCC) has known environmental risk factors, notably smoking, and enzymes that biotransform carcinogens have high levels of activity in the kidney. However, a possible role of polymorphisms in these enzymes in RCC etiology has received little study. We investigated glutathione S-transferase (GST) polymorphisms in a population-based case-control study of RCC. Subjects completed a structured interview, and DNA was isolated from pathological material or buccal cells for 130 cases, and from blood for 505 controls. Genotypes for GSTM1 and GSTT1 were determined by multiplex PCR, and for GSTP1 by oligonucleotide ligation assay. The frequency of GSTM1 null genotype was 50.0% in cases and 50.5% in controls, with an adjusted odds ratio (OR) of 1.0 [95% confidence interval (CI), 0.6-1.6]. For GSTP1, the frequencies of genotypes AA, AG, and GG representing the Ile104Val variant were: cases, 44.6%, 43.1%, and 12.3%; controls, 43.4%, 44.0%, and 12.6%; OR for AG and GG, 1.0 (95% CI, 0.6-1.6). An excess of the GSTT1 null genotype was observed in cases compared with controls, 28.6% versus 18.5% (OR, 1.9; 95% CI, 1.1-3.4). The association with GSTT1 was present among both smokers and nonsmokers, but was modified by body mass index, a recognized risk factor for RCC; among subjects in the lowest tertile of body mass index, the OR for GSTT1 null was 4.8 (95% CI, 1.8-13.0). The association between GSTT1 null and increased RCC risk in this population-based study suggests that activity of the GSTT1 enzyme protects against RCC. This contrasts with a recent report of reduced risk of RCC associated with GSTT1 null in a cohort of trichloroethene-exposed workers and suggests that specific chemical exposures alter the effect of GSTT1 on cancer risk.     

Glutathione S-transferase M1, T1, and P1 polymorphisms and survival among lung cancer patients.

Glutathione S-transferase (GST) enzymes detoxify therapeutic drugs and reactive oxidants, so GST polymorphisms may influence survival after diagnosis of cancer. We evaluated survival according to GST polymorphisms in a population-based series of lung cancer patients. The study subjects (n = 274) were men diagnosed with lung cancer from 1993 through 1996 who participated in a case control study and provided a blood sample for genotyping. The presence of the GSTM1 and GSTT1 genes were assayed by multiplex PCR. Genotype at the GSTP1 Ile(105)Val substitution was determined by PCR and oligonucleotide ligation assay. The study subjects were followed for vital status through 2000, and overall survival was evaluated in Kaplan-Meier survival functions and Cox proportional hazards models. Subjects with the GSTM1 null genotype had shorter survival; the proportion of GSTM1 null subjects surviving at 5 years was 0.20 [95% confidence interval (CI) 0.14-0.27], compared with 0.29 (95% CI 0.22-0.37) for GSTM1 present subjects. The relative risk of death associated with GSTM1 null genotype, adjusted for stage at diagnosis and histology, was 1.36, 95% CI 1.04-1.80. There was no association between GSTT1 or GSTP1 genotype and survival in the overall study population, nor in a subgroup of patients treated with chemotherapy (n = 130). For GSTM1, our results are consistent with a previous study, which also observed that the GSTM1-null genotype, which confers susceptibility to lung cancer, was associated with shorter survival. Future studies of lung cancer survival should take into account GSTM1 genotype as well as investigate underlying mechanisms.     

Glutathione s-transferase polymorphisms (GSTM1, GSTP1 and GSTT1) and the risk of acute leukaemia: a systematic review and meta-analysis

Glutathione s-transferase (GST) polymorphisms (GSTM1, GSTP1 and GSTT1) have been considered as risk factors for developing acute leukaemia in a number of studies; however the overall results of such studies are inconsistent. To investigate a putative association of GST polymorphisms with the risk of acute leukaemia, we performed a systematic review and meta-analysis of 30 published case-control studies. To take into account the possibility of heterogeneity across the studies, a statistical test was performed. The pooled odds ratios (ORs) were assessed using both a fixed-effects and a random-effects model. The pooled OR of acute leukaemia risks associated with GSTM1 null genotype, GSTP1 Val105 allele and GSTT1 null genotype were 1.22 (95% confidence interval (CI) 1.07-1.38), 1.07 (95% CI 1.00-1.13) and 1.19 (95% CI 1.00-1.41), respectively. Significantly increased risk of acute lymphoblastic leukaemia associated with GSTM1 and GSTT1 null genotypes was observed. Their pooled ORs were 1.24 (95% CI 1.17-1.31) and 1.30 (95% CI 1.06-1.60), respectively. We also found substantial evidence of heterogeneity between the studies. Our results suggest that GSTM1 and GSTT1, but not GSTP1 polymorphisms, appear to be associated with a modest increase in the risk of acute lymphoblastic leukaemia. It is conceivable that GSTM1 and GSTT1 null genotypes may thus play a role in leukemogenesis. A review of the 30 case-control studies indicates that greater attention should be paid to the design of future studies.     

A systematic approach to analysing gene-gene interactions: polymorphisms at the microsomal epoxide hydrolase EPHX and glutathione S-transferase GSTM1, GSTT1, and GSTP1 loci and breast cancer risk.

OBJECTIVE: We undertook a case-control study in an Australian Caucasian population-based sample of 1,246 cases and 664 controls to assess the roles of detoxification gene polymorphisms EPHX T>C Tyr(113)His, GSTT1 deletion, GSTM1 deletion, and GSTP1 A>G Ile(105)Val on risk of breast cancer. METHODS: We systematically addressed the main effects and possible gene-gene interactions using unconditional logistic regression to estimate odds ratios (OR) adjusted for potential confounders and using standard model building approaches based on likelihood theory. RESULTS: There was a decreased risk associated with the EPHX CC genotype [OR, 0.60; 95% confidence interval (95% CI), 0.43-0.84; P = 0.003], marginally significant evidence of increased risk with GSTM1 null genotype (OR, 1.21; 95% CI, 1.00-1.47; P = 0.05), but no association with GSTT1 null genotype (OR, 1.12; 95% CI, 0.86-1.45; P = 0.4) or GSTP1 (OR, 0.95; 95% CI, 0.82-1.10; P = 0.5) genotype. The full model with all interactions gave a significantly better fit than a main-effects-only model (P < 0.001), providing evidence for gene-gene interactions. The most parsimonious model included main effects for EPHX, GSTT1, and GSTM1; a two-way interaction between EPHX and GSTM1; and a three-way interaction between EPHX, GSTM1, and GSTT1. Predicted risks were greatest for women carrying deletions of both GSTT1 and GSTM1, with either the EPHX TC genotype (OR, 2.02; 95% CI, 1.19-3.45; P = 0.009) or EPHX CC genotype (OR, 3.54; 95% CI, 1.29-9.72; P = 0.14). CONCLUSION: Detoxification gene polymorphisms may interact with each other to result in small groups of individuals at modestly increased risk. We caution against overinterpretation and suggest that pooling of similarly large studies is needed to clarify the possible role of such complex gene-gene interactions on breast cancer risk. 2007;16(4):769-74).     

Glutathione S-transferase M3 (A/A) genotype as a risk factor for oral cancer and leukoplakia among Indian tobacco smokers

Polymorphism in glutathione S-transferase (GST) genes, causing variations in enzyme activities, may influence susceptibility to oral cancer and leukoplakia in smokers and/or smokeless tobacco users. In this case-control study consisting of 109 leukoplakia and 256 oral cancer patients and 259 controls, genotype frequencies at GSTM1, GSTT1, GSTM3 and GSTP1 loci were determined by polymerase chain reaction-restriction fragment length polymorphism methods and analyzed by multiple logistic regression to determine the risks of the diseases. There were no significant differences in the distributions of GSTM1, GSTM3 and GSTT1 genotypes in patients and controls when all individuals were compared. In contrast, frequencies of ile/ile genotype at codon 105 and variant val-ala haplotype of GSTP1 was significantly higher (OR = 1.5; 95% CI = 1.0-2.0) and lower (OR = 1.4; 95% CI = 1.0-1.9) in oral cancer patients compare to controls, respectively. The impacts of all genotypes on risks of oral cancer and leukoplakia were also analyzed in patients with different tobacco habits and doses. Increased risks of cancer and leukoplakia were observed in tobacco smokers with GSTM3 (A/A) genotype (OR = 2.0, 95% CI = 1.0-4.0; OR = 2.0, 95% CI = 1.0-4.4, respectively). So, GSTM3 (A/A) genotype could become one of the markers to know which of the leukoplakia would be transformed into cancer. Heavy tobacco chewing (> 124 chewing-year) increased the risk of cancer in individuals with GSTT1 homozygous null genotype (OR = 3.0; 95% CI = 1.0-9.8). Furthermore, increased lifetime exposure to tobacco smoking (> 11.5 pack-year) increased the risk of leukoplakia in individuals with GSTM1 homozygous null genotype (OR = 2.4; 95% CI = 1.0-5.7). It may be suggested that polymorphisms in GSTP1, GSTM1, GSTM3 and GSTT1 genes regulate risk of cancer and leukoplakia differentially among different tobacco habituals.     

Prognostic potential of glutathione S-transferase M1 and T1 null genotypes for gastric cancer progression

To improve understanding of glutathione S-transferase (GST) behavior in terms of a development and prognostic factor for gastric adenocarcinoma, we investigated the association between the GSTM1 and GSTT1 null genotypes and gastric cancer risk or the prognostic value of the GSTM1 and GSTT1 null genotypes was evaluated. Using a polymerase chain reaction-based method, the frequencies of GSTM1 and GSTT1 genotypes and prognostic factors, such as staging, differentiation, and histologic type (intestinal vs. diffuse), were evaluated in 80 patients with curatively resected primary gastric adenocarcinoma. The frequencies of GSTM1 and GSTT1 null individuals were higher in the gastric cancer group, but the differences were not statistically significant (for GSTM1 null odds ratio (OR)=0.86; 95% confidence interval (CI)=0.49-1.51 and for GSTT1, OR=0.97; 95% CI=0.55-1.71). Since the GSTM1 and GSTT1 null genotypes are potential indicators of gastric adenocarcinoma, we examined the relationship between the GSTM1 and GSTT1 genotypes and prognostic factors. In terms of the histologically diffuse type of cancer, GSTM1 indicated an approximately 3.24-fold increase (OR=3.24; 95% CI=1.05-10.17). With respect to gastric cancer differentiation, the frequency of the GSTM1 null genotype was linked with a statistically significant increase in risk (3.42-fold) for the high-grade type (OR=3.42; CI=1.02-13.24). Our results indicate that there is no obvious relationship between GSTM1 and GSTT1 polymorphisms and the development of gastric cancer. However, in Korean gastric adenocarcinoma patients the GSTM1 null genotype appears to be associated with a poorer prognosis.     

Genetic determinants in the metabolism of bladder carcinogens in relation to risk of bladder cancer

Genetically determined factors that alter the metabolism of tobacco carcinogens can influence an individual's susceptibility to bladder cancer. The associations between the genotypes of glutathione S-transferase (GST) M1, GSTP1, GSTT1 and N-acetyltransferase (NAT) 1 and the phenotypes of NAT2 and cytochrome P450 (CYP) 1A2 and bladder cancer risk were examined in a case-control study involving 731 bladder cancer patients and 740 control subjects in Los Angeles County, California. Individual null/low-activity genotypes of GSTM1, GSTT1 and GSTP1 were associated with a 19-48% increase in odds ratio (OR) of bladder cancer. The strongest association was noted for GSTM1 [OR for the null genotype = 1.48, 95% confidence interval (CI) = 1.19-1.83]. When the three GST genes were examined together, there was a monotonic, statistically significant association between increasing number of null/low-activity genotypes and risk (P for trend = 0.002). OR (95% CI) for one and two or more null/low-activity GST genotypes was 1.42 (1.12-1.81) and 1.71 (1.25-2.34), respectively, relative to the absence of null/low-activity GST genotype. NAT2 slow acetylation was associated with doubled risk of bladder cancer among individuals with known high exposures to carcinogenic arylamines (OR = 2.03, 95% CI = 1.12-3.69, P = 0.02). The effect of NAT2 slow acetylation was even stronger in the presence of two or more null/low-activity GST genotypes. There were no associations between bladder cancer risk and NAT1 genotype or CYP1A2 phenotype.     

Glutathione S-Transferase P1 Variant Plays a Major Contribution to Decreased Susceptibility to Liver Cancer in Thais

Glutathione S-transferases (GSTs) play important roles in carcinogenic biotransformation processes, whichvary among individuals. Polymorphisms of the encoding genes are associated with alteration of detoxificationcapacity, resulting in a variable risk of cancer development. The present study was performed to determine theeffects of polymorphisms in GST (M1, P1, and T1) genes on susceptibility to liver cancer in Thais. We recruited140 hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patients and 280 healthy volunteers forour unmatched case-control based association study. GSTM1 deletion and heterozygous deletion were determinedand discriminated by semi-quantitative denaturing high performance liquid chromatography (DHPLC). Apolymerase chain reaction - restriction fragment length polymorphisms (PCR-RFLPs) approach was utilized todetect the GSTP1 Ile105Val variant, while the GSTT1 null allele was detected by multiplex PCR. With resultsfor single locus associations, only GSTP1 Ile/Val showed a significant decrease in the risk of liver cancer (OR=0.58;95% CI: 0.36-0.90; p-value=0.016). GSTP1 (Ile/Val) interacted with the GSTT1 wild type to further decreasesusceptibility to liver cancer (OR=0.41; 95% CI: 0.18-0.93; p-value=0.029). Moreover, three locus interactionsof GSTP1 (Ile/Val or Val/Val) with either wild type or null alleles of both GSTM1 and GSTT1 decreased risk ofliver cancer. In conclusion the GSTP1 null genotype apparently causes decreased risk of liver cancer in Thais.The findings point to GSTP1 Ile105Val as a possible protective allele against liver cancer risk.     

Glutathione S-transferase M1 and T1 null genotypes and the risk of gastric and colorectal cancers.

Several polymorphic glutathione S-transferase (GST) enzymes are involved in the detoxification of active metabolites of many potential carcinogens and may therefore be important in modulating susceptibility to cancers. GSTM1 and GSTT1 are polymorphic, and the null alleles result in a lack of corresponding enzyme activities. Previous studies demonstrated that the GSTM1 and GSTT1 null genotypes correlated with an increased risk of developing some cancers. In this study, we determined GSTM1 and GSTT1 polymorphisms in a population of 131 healthy controls from the south of Iran, 46 patients with colorectal cancers, and 42 patients with gastric cancer. The gastric cancer risk statistically increased due to the GSTM1 null genotype (odds ratio (OR)=2.3, 95% confidence interval (CI): 1.15--4.95). On the other hand, the GSTT1 null genotype in gastric cancer and null genotypes of GSTM1 and GSTT1 in colorectal cancer were not statistically significant. Moreover, individuals showing the GSTM1 and GSTT1 null genotypes might exhibit a greater predisposition to gastric (OR=3.31, 95% CI: 1.14--9.57) and colorectal (OR=2.73, 95% CI: 0.94--7.95, P=0.07) cancers.     

Genetic Polymorphism of GSTP1, GSTM1 and GSTT1 Genes and Susceptibility to Chronic Myeloid Leukaemia

Background: The development of cancer results from an imbalance between exposure to carcinogens and the capacity of various enzyme systems engaged in activation or in the detoxification of xenobiotics. The aim of the present study is to investigate the association of GSTP1, GSTM1 and GSTT1 gene polymorphisms in susceptibility to Chronic Myeloid Leukaemia (CML). Methods: A total of 200 CML patients and 100 controls were enrolled in a case-control study with GSTM1 and GSTT1 analysis with PCR and GSTP1 analysis with PCR-RFLP. Results: The GSTT1 null genotype was significantly higher among CML patients suggesting that this genotype is associated with an increased risk of CML. It was found in 42% of cases as compared with 21% of the controls, (OR =2.78, 95% CI: 1.59 - 4.85; p-value =0.000). The presence of the GSTT1 genotype may thus be considered a protective factor for CML. The frequency of individuals carrying GSTM1 null genotype was slightly higher in the control group but this difference was not statistically significant. The GSTM1 null genotype was present in 35% of control cases and 34% of the CML patients, (OR=0.975, 95%CI: 0.58-1.58;p-value=0.863). Individuals with a combined GSTM1 null/GSTT1null genotype had an estimated 2.85-fold increased risk of CML, but no associated risk between GSTP1 Ile 105 Val polymorphism and CML was found (OR=1.99, 95% CI: 0.40 - 9.32; p-value = 0.417). Conclusions: No association between GSTP1 and GSTM1 with susceptibility to CML was found. GSTT1 genotype may be a protective factor for CML, while the null genotype shows association with developing CML.