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.     

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.     

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.     

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.     

Glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes and the risk of smoking-related oral and pharyngeal cancers

Several polymorphic glutathione S-transferase enzymes are involved in the detoxification of active metabolites of many potential carcinogens from tobacco smoke and may therefore be important in modulating susceptibility to smoking-related cancers. As part of a hospital-based case-control study performed in France among Caucasian smokers, we studied GSTM1, GSTM3, GSTP1 and GSTT1 gene polymorphisms in 121 patients with oral cavity and pharyngeal cancers and 172 hospital controls using peripheral blood DNA. An increase in risk was found among carriers of the GSTP1 (AG or GG) genotype (OR 1.6, 95% CI 1.0-2.8, p = 0.07) or the GSTT1 null genotype (OR 2.0, 95% CI 1.0-4.0, p = 0.05). The effect of these at-risk genotypes was most marked in subjects with a history of more than 30 years of smoking, among whom the respective ORs were 2.0 (95% CI 1.0-3.9) and 3.3 (95% CI 1.3-8.1), though the interaction tests between these genotypes and duration of smoking were not significant. In contrast, neither the GSTM1 null genotype nor the GSTM3 AA genotype was associated with oropharyngeal cancer risk (OR 0.9, 95% CI 0.5-1.5 and OR = 1.3, 95% CI 0.7-2.3, respectively). Our results thus suggest that GSTP1 and GSTT1 gene polymorphisms modulate susceptibility to smoking-related cancers of the oral cavity and pharynx.     

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).     

Meta-analysis of the association between GSTM1 and GSTT1 gene polymorphisms and cervical cancer

Aim: We conducted a meta-analysis to analyze the influence of GSTM1 and GSTT1 gene polymorphisms on cervical cancer risk, and explore gene-environment interactions. Methods: Identification of relevant studies was carried out through a search of Medline and the EMbase up to Oct. 2011. All case-control studies that investigated the association between GSTM1 and GSTT1 gene polymorphisms and risk of cervical cancer were included. The pooled odds ratio (OR) was used for analyses of results and the corresponding 95% confidence intervals (CI) were estimated. Results: A total of 21 case-control studies were included in the meta-analysis of GSTM1 (2,378 cases and 2,639 controls) and GSTT1 (1,229 cases and 1,223 controls) genotypes. The overall results showed that the GSTM1 null was related to an increased risk of cervical cancer (OR=1.50, 95% CI=1.21-1.85). Subgroup analysis were performed based on smoking and ethnicity. Our results showed that smokers with null GSTM1 genotype had a moderate increased risk of cervical cancer (OR=1.85, 95% CI=1.07-3.20). For the ethnicity stratification, moderate significantly increased risk of null GSTM1 genotype was found in Chinese (OR=2.12, 95% CI=1.43-3.15) and Indian populations (OR=2.07, 95% CI=1.49-2.88), but no increased risk was noted in others. Conclusion: This meta-analysis provided strong evidence that the GSTM1 genotype is associated with the development of cervical cancer, especially in smokers, and Chinese and Indian populations. However, no association was found for GSTT1 null genotype carriers.     

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.     

Association of GSTM1, GSTT1, GSTM3, and GSTP1 Genes Polymorphisms with Susceptibility to Osteosarcoma: a Case- Control Study and Meta-Analysis

Background: Some studies have investigated the association of GSTM1, GSTT1, GSTM3, and GSTP1polymorphisms with susceptibility to osteosarcoma; however, these studies results are inconsistent and inconclusive. Inorder to drive a more precise estimation, the present case-control study and meta-analysis was performed to investigateassociation of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with osteosarcoma. Methods: Eligible articleswere identified by a search of several electronic databases for the period up to May 5, 2018. Odds ratios were pooledusing either fixed-effects or random effects models. Results: Finally, a total of 24 case-control studies with 2,405osteosarcoma cases and 3,293 controls were included in the present meta-analysis. Overall, significantly increasedosteosarcoma risk was found when all studies were pooled into the meta-analysis of GSTT1 (Null vs. Present: OR= 1.24795% CI 1.020-1.524, P= 0.031) and GSTP1 polymorphism (B vs. A: OR= 8.899 95% CI 2.722-29.094, P≤0.001). Inthe stratified, significantly increased osteosarcoma risk was observed for GSTT1 polymorphism among Asians (Nullvs. Present: OR= 1.300 95% CI 1.034-1.635, P= 0.025), but not among Caucasians. Conclusions: This meta-analysisdemonstrated that GSTP1 and GSTT1 null genotype are associated with the risk of osteosarcoma. Future large welldesigned epidemiological studies are warranted to validate our results.     

GSTM1, GSTT1, and GSTP1 polymorphism and lung cancer risk in relation to tobacco smoking

The impact of genetic polymorphisms in GSTM1, GSTP1 or GSTT1 on susceptibility to lung cancer has received particular interest since these enzymes play a central role in detoxification of major classes of tobacco carcinogens. In the current German study we investigated the role of GSTM1, GSTT1 and GSTP1 polymorphisms as a genetic modifier of risk for individuals with lung cancer as susceptible genotypes especially in relation to tobacco smoking. The GSTM1, the GSTP1 as well as GSTT1-polymorphism were determined by real time PCR analysis in 446 lung cancer patients and 622 controls. The observed allele frequencies of the GSTP1 polymorphism in the population were within the range described for Caucasians. Multivariate analyses of lung cancer patients, who carried at least one mutant variant allele of GSTP1 (OR=1.03; 95%-CI: 0.76-1.39) did not show any elevated risks. GSTM1 or GSTT1 null-genotypes were found in 47.3% resp. 18.5% of the controls and in 52.5% resp. 16.8% of the cancer patients. The estimated risk of the GSTM1 null genotype for lung cancer was OR=1.34 (95%-CI: 0.99-1.81) and for the GSTT1 null genotype OR=0.88 (95%-CI: 0.59-1.32). When analyzed by histology no individual subtype of lung cancer was strongly associated with the polymorphisms. Lung cancer risk rose significantly with higher cumulative cigarette consumption confirming the association with smoking-related lung cancer risk. Stratified analysis between tobacco smoking and variant genotypes revealed for heavy smokers (>60 pack-years) increasing risks at the presence for at least one copy of the GSTP1 variant allele OR=50.56 (95%-CI: 15.52-164.79). The corresponding risks for GSTM1 null genotypes were OR=112.08 (95%-CI: 23.02-545.71) and for the GSTT1 null-genotype OR=158.49 (95%-CI: 17.75-1415.06) in smokers >60 pack-years. Analysing the interaction between tobacco smoking and the genotypes, combined smoking and having the susceptible genotypes did not show a joint effect. In this study polymorphisms of the GSTM1, GSTT1 or GSTP1 had no relevant modifying effect on lung cancer risk and cumulative smoking dose.     

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 gene polymorphisms and risk of gastric cancer in a Chinese population

Aim: The potential role of GSTM1, GSTT1 and GSTP1 polymorphisms in risk of gastric cancer in Chinese was studied. Methods: We collected 194 gastric cancers by pathologic examination and 412 controls from southern China during January 2007 to January 2011. Genotyping was based upon duplex polymerase-chain-reaction withthe PCR-CTPP method. Results: Individuals carrying null GSTM1 and GSTT1 had 1.49 and 1.96 fold risk sof gastric cancer when compared with respective non-null genotypes. We also found a non-significant 37% excess risk of gastric cancer among carriers of GSTP1 1b/1b genotype when compared with 1a/1a genotype (OR=1.37, 95% CI=0.81-2.25). The combination of null/null GSTM1 and GSTT1 genotypes showed higher increased risk of gastric cancer (OR=3.17, 95% CI=1.68-4.21). Moreover, cancers in ever smokers and ever drinkers were observed to be strongly associated with null GSTM1 and GSTT1, and a significant cancer risk was observed in positive H.pylori infection individuals with null GSTT1. Conclusion: Our study provided evidence that genetic deletion of GSTM1 and GSTT1 may contribute to increased susceptibility to gastric cancer in our Chinese population, while the GSTP1a/b polymorphism may not.     

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.     

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.     

Polymorphisms in GSTM1, GSTTI and GSTP1 and nasopharyngeal cancer in the east of China: a case-control study

Aim: The study was performed to assess the potential role of GSTM1, GSTT1 and GSTP1 polymorphisms in the risk of nasopharyngeal cancer in Chinese population. Method: We collected 182 cases undergoing pathologic examination and 366 controls from the affiliated hospital of Medical College of Qingdao University from April 2006 to July 2010. Genotyping was based upon duplex polymerase-chain-reactions with the PCR-CTPP method. Results: More smokers were found in NPC patients than controls, and a higher IgA/VCA+ . Individuals carrying null GSTM1 and GSTT1 had 1.76 and 2.01 fold risk of NPC when compared with non-null genotypes, respectively. A non-significant increase risk of NPC was found in individuals with 1b/1b genotype when compared with 1a/1a genotype (OR=1.32, 95%CI=0.60-2.94). When compared with non-null GSTM1 and GSTT1 genotypes, the combination of null/null GSTM1 and GSTT1 genotypes showed moderate increased risk of NPC (OR=3.03, 95% CI=1.74-5.08). Conclusion: Our study provides evidence that genetic deletion of GSTM1 and GSTT1 may contribute to increased susceptibility to NPC in Chinese population, while GSTP1 may not. Our findings provide information relevant to the prevention of NPC.     

Lung cancer susceptibility and polymorphisms of glutathione-S-transferase genes in Hong Kong

OBJECTIVE: To study the potential role of genetic polymorphisms of glutathione-S-transferases GSTM1, GSTT1 and GSTP1 in susceptibility to lung cancer in Hong Kong Chinese. METHODS: 229 consecutive incident patients with a histological diagnosis of lung cancer from a regional hospital and 197 healthy population-based controls were recruited for this study between July 1999 and June 2001. Genetic polymorphisms of GSTT1 and GSTM1 were determined using PCR-based technique. RESULTS: The frequencies of GSTT1 and GSTM1 null genotypes were 51.8 and 59.4% in healthy controls and 63 and 54.7%, respectively, in lung cancer patients. GSTP1 Val105/Val105 genotype was found in only 1% of healthy controls. The risk for lung cancer with GSTT1 null genotype was significantly higher, adjusted odds ratio (OR) 1.69, 95% confidence interval (CI) 1.12-2.56, compared with those with the GSTT1 genotype; the increase in risk was found only in non-smokers. GSTM1 null genotype, combined GSTT1 and GSTM1 null genotype and GSTP1 Val105/Val105 genotype did not confer any increase risk for lung cancer. CONCLUSION: GSTT1 null genotype is associated with an increased risk for lung cancer in non-smoking Chinese in Hong Kong.     

Risk Effects of GST Gene Polymorphisms in Patients with Acute Myeloid Leukemia: A Prospective Study

Glutathione S-transferase (GST) enzyme levels are associated with risk of many cancers, including hematologictumours. We here aimed to investigate the relationships between GSTM1, GSTT1 and GSTP1 polymorphisms andthe risk of AML. Genotyping of GSTs was based upon duplex polymerase-chain-reactions with the confrontingtwo-pair primer (PCR-CTPP) method in 163 cases and 204 controls. Individuals carrying null GSTT1 genotypehad a 1.64 fold risk of acute leukemia relative to a non-null genotype (P<0.05). A heavy risk was observed inthose carrying combination of null genotypes of GSTM1 and GSTT1 and GSTP1 Val allele genotypes whencompared with those carrying wild genotypes, with an OR (95% CI) of 3.39 (1.26-9.26) (P<0.05). These findingsindicate that genetic variants of GST and especially the GSTT1 gene have a critical function in the developmentof AML. Our study offers important insights into the molecular etiology of AML.     

Glutathione S-transferase polymorphisms and oral cancer: a case-control study in Rio de Janeiro, Brazil

This study evaluates the influence of genetic polymorphisms at GSTM1, GSTT1 and GSTP1 gene loci on oral cancer susceptibility among Brazilians from Rio de Janeiro. DNA extracted from white blood cells of 231 oral cancer patients and 212 hospital controls was analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. GSTM1 polymorphism distribution was different between cases and controls (P=0.006), with an overrepresentation of GSTM1 A/B genotype in controls. GSTM1 A/B individuals were at decreased oral cancer risk (OR=0.08; 95% CI=0.05-0.62). No statistically significant association was observed for GSTT1 and GSTP1 polymorphisms. Differences in the GSTM1 and GSTT1 null genotype frequencies were observed between individuals of European origin and African origin, but these genotypes do not seem to influence the risk of oral cancer. Therefore, these results do not support the hypothesis of increased risk of GSTP1 G/G, GSTM1 or GSTT1 null genotypes for developing cancer in oral cavity, but the GSTM1 A/B genotype emerged as a protective factor.     

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.     

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.