GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer

It is likely that heritable genetic factors contribute to the development of endometriosis, which is a putative precursor of the endometrioid and clear cell histological subtypes of ovarian cancer. The phase II glutathione S-transferases (GSTs) are a family of enzymes responsible for metabolism of a broad range of xenobiotics and carcinogens. Allelic variants of GSTs that have impaired detoxification function may increase the rate of genetic damage and thereby increase the susceptibility to cancer. The null genetic polymorphism in the gene encoding the GST class mu (GSTM1) enzyme has been reported to be significantly elevated in endometriosis patients and may represent an endometriosis susceptibility allele. In this study the frequency of the GSTM1 null genotype was investigated in 84 cases of endometriosis, 293 cases of ovarian cancer and 219 controls. All cases and controls were derived from women resident in the south east of England. The frequency of the GSTM1 null allele was not over-represented in the endometriosis patients (47.6%) compared with the controls (48.9%) (P = 0.898). In the ovarian cancer group the GSTM1 null genotype was significantly elevated compared with controls (59.0 versus 48.9%, P = 0.025). When stratified according to histological subtype a significantly increased GSTM1 null genotype was only observed for the endometrioid (65.4%, P = 0.013) and the combined endometrioid/clear cell ovarian cancers (67.0%, P = 0.004). We conclude that the GSTM1 null allele is not an endometriosis susceptibility allele, however, it may predispose endometriotic lesions to malignant transformation to endometrioid and clear cell ovarian cancer.     

The role of glutathione-S-transferase polymorphisms in ovarian cancer survival

Resistance to chemotherapy represents one of the most important causes of treatment failure in patients with ovarian cancer. Common polymorphisms in the glutathione-S-transferase (GSTM1, GSTP1 and GSTT1) family have been implicated in chemoresistence and ovarian cancer survival. In this study, we have analysed Australian women diagnosed with primary invasive epithelial ovarian cancer between 1985 and 1997, using DNA extracted from peripheral blood and archival uninvolved (normal) tissues. GSTP1 genotypes were determined using ABI Prism 7700 Sequence Detection System methodology (n=448) and GSTT1 and GSTM1 genotypes using PCR-agarose methodology (n=239). We observed a significant survival advantage among carriers of GSTP1 Ile105Val GG/GA genotype (HR 0.77, 95% confidence interval (CI) 0.61-0.99,p=0.04) and a non-significant survival advantage among women who were homozygous for the GSTM1 and GSTT1 deletion variants. There was also evidence of an additive effect, with a stronger survival benefit in women carrying three low function GST genotypes (GSTM1 null, GSTT1 null and GSTP1 GA/GG) (HR 0.47, 95% CI 0.22-1.02). The results of this study, the largest to date, are consistent with a number of previous smaller studies which have also observed that reduced GST function was associated with better survival outcomes in patients with ovarian cancer.     

Glutathione S-transferase T1 null-genotype is associated with an increased risk of lung cancer

Glutathione S-transferases (GSTs) are involved in detoxification of carcinogens, e.g., from tobacco smoke. Therefore, polymorphisms in the GST genes have been considered as potential modifiers of individual cancer risk. In a population-based case-cohort study where cases and the subcohort sample were matched on duration of smoking, we investigated the occurrence of lung cancer and histological subtypes of lung cancer in relation to deletion polymorphism in both GSTM1 and GSTT1, single nucleotide polymorphisms (SNPs) in GSTP1 (Ile105Val and Ala114Val) and a 3 base pair deletion polymorphism in GSTM3. We further investigated the effects of the GST polymorphisms on lung cancer risk within subgroups of subjects defined by gender and age. The results showed a 2.4-fold (CI = 1.31-4.41) increased risk of lung cancer in GSTT1 null-genotype carriers but no significant effects of the polymorphisms in GSTM1, GSTM3, GSTP1-105 or GSTP1-114. The association was strongest in lower age groups, with a 9.6-fold increase in risk for subjects with the GSTT1 null-genotype in the 50-55 years age interval (CI = 3.03-30.59). Positive associations were found for GSTT1 within all major histological subtypes. Squamous cell carcinoma was the histological type most strongly associated with the GSTT1 genotype, with a 5.0-fold (CI = 2.26-11.18) increase in risk for subjects carrying the GSTT1 null-genotype. The effects of the GSTT1 null-genotype seemed stronger in the presence of the GSTM1 null-genotype or the GSTP1-105 variant allele. These results suggest that the GSTT1 null-genotype is associated with an increased risk of lung cancer, especially in younger individuals.     

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, T1 and P1 polymorphisms: susceptibility and outcome in lung cancer patients

The glutathione S-transferases (GSTs) are a superfamily of genes whose products are phase II enzymes, catalyzing the conjugation of reactive intermediates to soluble glutathione. Some of the GSTs are polymorphic and may play a role in lung cancer susceptibility. We investigated whether genetic polymorphisms of GSTM1, GSTP1 and GSTT1 genes modulated lung cancer risk and affect survival among lung cancer patients. We determined the GST genotypes in 422 study subjects, using polymerase chain reaction (PCR) and reverse PCR and restriction fragment length polymorphism (RFLP). Logistic Regression analysis was carried out to find the association of various polymorphisms and GSTs and lung cancer. The influence of the genetic polymorphisms on patient survival was estimated using the method of Kaplan-Meier survival function. Cox Proportional Hazard models were used to estimate hazard ratios (HR) for deaths. GSTT1 -/- genotype conferred a higher odds ratio of 2.9 (P = 0.001) compared to the GSTT1+/+. So also, the GSTP1 GG genotype too had higher risk compared to the GSTP1 AA genotype (OR = 2.3, P = 0.033). When the combined GST M1, GSTT1 and GSTP1 genotypes were examined, patients with the combinations GSTM1 null and GSTT1 null had a significant OR of 3.6. So also the combinations GSTT1-/- GSTP1 AA (P = 0.005) and GSTT1-/- GSTP1 AG/GG (P = 0.001) came out to be significant. There were some significant interactions between GST genotypes with tobacco smoking and also for clinicopathological factors. Regarding survival analysis, no association of GSTM1 or GSTP1 genes with survival was noted. The GSTT1 -/- genotype along with stage was significantly associated with overall survival and found to be an independent prognostic factors for shorter lung cancer survival.     

A population-based study of glutathione S-transferase M1, T1 and P1 genotypes and risk for lung cancer

A deletion polymorphism for glutathione S-transferase M1 (GSTM1) has been related to risk for lung cancer among smokers in some studies but not in others. We examined GSTM1, a GSTT1 deletion polymorphism and a common GSTP1 gene variant (iso→val), as risk factors for lung cancer in a population-based case-control study of men. Cases (N=274) were males identified from 1993 to 1996 through the Fred Hutchinson Cancer Research Center Cancer Surveillance System registry for western Washington State. Male age-matched controls (N=501) were selected by random-digit dialing. Subjects participated in a telephone interview and blood draw. GSTM1 and GSTT1 were genotyped with a multiplex PCR assay using beta-globin as a positive control, and GSTP1 single nucleotide variant determined with PCR-based oligonucleotide ligation assays. GSTM1 absence was associated with a modest elevation in risk among all cases (odds RATIO=1.27, 95% CI 0.91–1.77) and among non-small cell cancers (adenocarcinoma OR=1.58, 95% CI 0.99–2.52; squamous cell OR=1.40, 95% CI 0.83–2.34). Risk associated with GSTM1 null was increased two to sixfold among heavy smokers. GSTT1 was not associated with lung cancer risk and GSTP1 val was non-significantly associated with a modest reduction in risk, particularly among heavy smokers. No specific combination of GST genotypes was particularly associated with risk. These results support previous reports that the GSTM1 null genotype is associated with a modest increase in risk for lung cancer, particularly among heavy smokers, suggest no role for GSTT1 and the need for further study of GSTP1.     

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.     

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.     

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 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.     

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.     

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.     

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.     

Genetic polymorphisms of glutathione-S-transferase genes (GSTM1, GSTT1 and GSTP1) and upper aerodigestive tract cancer risk among smokers, tobacco chewers and alcoholics in an Indian population

The glutathione-S-transferase (GST) genes are involved in the detoxification of various carcinogens that increase the risk to upper aerodigestive tract (UADT) cancers. In the present study, 408 unrelated histopathologically confirmed cases and 220 population based controls, matched by age and gender, which belonged to the Tamilian population of south India were genotyped for polymorphisms in GSTM1, GSTT1 and GSTP1 using polymerase chain reaction (PCR) based methods. The multivariate logistic regression analyses demonstrated that GSTT1 null genotype was significantly associated with increased risk for UADT cancers (odds ratio (OR) 2.5; 95% confidence intervals (CIs) 1.3–4.7). The combined effects of GST genes have shown that concurrent lack of GSTM1 and GSTT1 had a significantly increased risk (OR 4.6; 95% CI 1.3–15.6), while GSTT1 null genotype along with GSTP1 polymorphic variants further increased the cancer risk (OR 5.3; 95% CI 2.0–13.6). The most remarkable risk was seen among individuals carrying GSTM1 null, GSTT1 null genotypes and GSTP1 polymorphic variants (OR 7.8; 95% CI 1.0–61.0). Tobacco chewers carrying GSTM1 null genotype had an enhanced risk for UADT cancers. An enhanced risk among tobacco chewers and alcoholics (regular) was noted in individuals with GSTT1 null genotype. Similarly, a significant interaction was observed among smokers (>40 pack-year (PY)) and tobacco chewers carrying GSTP1 mutant genotypes. Although the null genotype of GSTT1 is a strong predisposing risk factor for UADT cancers, we conclude that the significant gene–gene and gene–environment interactions of GST genes may confer a substantial risk to UADT cancers in the Tamilian population of south India.     

Lack of Any Association of GST Genetic Polymorphisms with Susceptibility to Ovarian Cancer - a Meta-analysis

Objective: Epidemiology studies have reported conflicting results between glutathione S-transferase Mu-1 (GSTM1), glutathione S-transferase theta-1 (GSTT1) and glutathione S-transferase pi-1 (GSTP1) and ovarian cancer (OC) susceptibility. In this study, an updated meta-analysis was applied to determine whether the deletion of GSTM1, GSTT1 and GSTP1 has an influence on OC susceptibility. Methods: A published literature search was performed through PubMed, Embase, Cochrane Library, and Science Citation Index Expanded database for articles published in English. Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated using random or fixed effects models. Heterogeneity between studies was assessed using the CochraneQ test and I2 statistics. Sub-group analysis was conducted to explore the sources of heterogeneity. Sensitivity analysis was employed to evaluate the respective influence of each study on the overall estimate. Results: In total, 10 published studies were included in the final analysis. The combined analysis revealed that there was no significant association between GSTM1 null genotype and OC risk (OR=1.01, 95%CI: 0.91-1.12). Additionally, there was no significant association between GSTT1 genetic polymorphisms and OC risk (OR=0.98, 95% CI: 0.85-1.13). Similalry, no significant associations were found concerning the GSTP1 rs1695 locus and OC risk. Meanwhile, subgroup analysis did not show a significant increase in eligible studies with low heterogeneity. However, sensitivity analysis, publication bias and cumulative analysis demonstrated the reliability and stability of the current meta-analysis. Conclusions: These findings suggest that GSTs genetic polymorphisms may not contribute to OC susceptibility. Large epidemiological studies with the combination of GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphisms and more specific histological subtypes of OC are needed to prove our findings.     

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.     

Glutathione S-transferase T1 and M1 gene defects in ovarian carcinoma

Glutathione S-transferases (GSTs) M1 and T1 are known to be polymorphic in humans. Both polymorphisms are due to gene deletions, which are responsible for the existence of null genotypes. The gene defect of GSTT1 has been reported to be associated with an increased risk of myelodysplastic syndromes, astrocytoma and meningioma. A lack of GSTM1 was associated with tobacco smoke-induced lung and bladder cancer. In this study we examined whether the GSTT1 and/or GSTM1 homozygous null genotypes were associated with an increased risk of ovarian cancer using a multiplex polymerase chain reaction protocol. The GSTT1 null genotype was observed in 14% of the control subjects that had never suffered from neoplastic disease (n=115) and in 16% of the patients affected with ovarian cancer (n=103, OR 0.87, 95% CI 0.39–1.92, P=0.73). A lack of GSTM1 was observed in 38% of the control subjects and in 46% of the patients (OR 0.77, 95% CI 0.44–1.32). This difference was not significant (P=0.34). Similarly, no significant differences were obtained if GSTT1 and/or GSTM1 null genotypes were analyzed in subgroups of control subjects and ovarian cancer patients between the ages of 20–40, 41–70 and 71–90 years and in individuals with a positive family history of neoplastic disease. GSTT1 and/or GSTM1 null genotypes were not significantly associated with the histologic type and grade or FIGO (International Federation of Gynecology and Obstetrics) stages of the ovarian carcinomas. In conclusion, GSTT1 and/or GSTM1 null genotypes are not markers for an increased risk of ovarian cancer.     

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.     

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.     

Genetic polymorphisms of glutathione S-transferases as modulators of lung cancer susceptibility

Some of the glutathione S-transferases (GSTs) are polymorphic and may play a role in lung cancer susceptibility. Our previous study in a French Caucasian study population suggested GSTM1 null genotype as a moderate risk factor for lung cancer. Here we extended the study to investigate the potential role of GSTT1 and GSTP1 polymorphisms in susceptibility to lung cancer, either separately or in combination. The study population consisted of 268 controls and 251 cases. Nineteen percent of the controls and 15% of the cases had GSTT1 null genotype. The distribution of GSTP1*A/*A, *A/*B and *B/*B genotypes were 46.9, 45.5 and 7.6% in controls, and 47.8, 40.2 and 12.0% in cases, respectively. No statistically significant effects in the lung cancer risk were observed for the GSTT1 genotypes, but the GSTP1*B/*B genotype posed a 2-fold risk [odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.0-4.1] of this malignancy compared with the GSTP1*A allele containing genotypes; this association was mainly attributable to small cell lung cancer (OR = 3.6, 95% CI 1.3-9.8). The most remarkable risk was seen for the small cell carcinoma among subjects with the GSTP1*B/*B genotype and concurrent lack of the GSTM1 gene (OR = 6.9, 95% CI 1.6-30.2). The deficient genotypes for GSTM1 and GSTP1 seem thus to be important risk modifiers for lung cancer, especially in combination.