Glutathione-S-transferase (GST) polymorphisms are associated with relapse after radical prostatectomy.
ABSTRACT: Organ confined prostate cancer (PCa) can be cured by radical retropubic prostatectomy (RRP); however, some tumors will still recur. Current tools fail to identify patients at risk of recurrence. Glutathione-S-transferases (GSTs) are involved in the metabolism of carcinogens, hormones and drugs. Thus, genetic polymorphisms that modify the GST activities may modify the risk of PCa recurrence.We retrospectively recruited Argentine PCa patients treated with RRP to study the association between GST polymorphisms and PCa biochemical relapse after RRP. We genotyped germline DNA in 105 patients for: GSTP1 c.313A>G (p.105 Ile>Val, rs1695) by PCR-RFLP; and GSTT1 null and GSTM1 null polymorphisms by multiplex PCR. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate these associations.Patients with GSTP1 c.313GG genotype showed shorter biochemical relapse-free survival (BRFS) (P = 0.003) and higher risk for recurrence in unadjusted (Hazard ratio (HR) = 3.16, 95% confidence interval (95% CI) = 1.41-7.06, P = 0.005) and multivariate models (HR = 3.01, 95% CI = 1.13-8.02, P = 0.028). We did not find significant associations for GSTT1 and GSTM1 genotypes. In addition, we found shorter BRFS (P = 0.010) and increased risk for recurrence for patients having two or more risk alleles when we combined the genotypes of the three GSTs in multivariate models (HR = 3.06, 95% CI = 1.20-7.80, P = 0.019).Our results give support to the implementation of GSTs genotyping for personalized therapies as a novel alternative for PCa management for patients who undergo RRP. To the best of our knowledge, this is the first study that examined GST polymorphisms in PCa progression in Argentine men. Replication of our findings in larger cohort is warranted.
Project description:BACKGROUND:Polymorphisms in glutathione S-transferase (GST) genes may influence response to oxidative stress and modify prostate cancer (PCA) susceptibility. These enzymes generally detoxify endogenous and exogenous agents, but also participate in the activation and inactivation of oxidative metabolites that may contribute to PCA development. Genetic variations within selected GST genes may influence PCA risk following exposure to carcinogen compounds found in cigarette smoke and decreased the ability to detoxify them. Thus, we evaluated the effects of polymorphic GSTs (M1, T1, and P1) alone and combined with cigarette smoking on PCA susceptibility. METHODS:In order to evaluate the effects of GST polymorphisms in relation to PCA risk, we used TaqMan allelic discrimination assays along with a multi-faceted statistical strategy involving conventional and advanced statistical methodologies (e.g., Multifactor Dimensionality Reduction and Interaction Graphs). Genetic profiles collected from 873 men of African-descent (208 cases and 665 controls) were utilized to systematically evaluate the single and joint modifying effects of GSTM1 and GSTT1 gene deletions, GSTP1 105 Val and cigarette smoking on PCA risk. RESULTS:We observed a moderately significant association between risk among men possessing at least one variant GSTP1 105 Val allele (OR = 1.56; 95%CI = 0.95-2.58; p = 0.049), which was confirmed by MDR permutation testing (p = 0.001). We did not observe any significant single gene effects among GSTM1 (OR = 1.08; 95%CI = 0.65-1.82; p = 0.718) and GSTT1 (OR = 1.15; 95%CI = 0.66-2.02; p = 0.622) on PCA risk among all subjects. Although the GSTM1-GSTP1 pairwise combination was selected as the best two factor LR and MDR models (p = 0.01), assessment of the hierarchical entropy graph suggested that the observed synergistic effect was primarily driven by the GSTP1 Val marker. Notably, the GSTM1-GSTP1 axis did not provide additional information gain when compared to either loci alone based on a hierarchical entropy algorithm and graph. Smoking status did not significantly modify the relationship between the GST SNPs and PCA. CONCLUSION:A moderately significant association was observed between PCA risk and men possessing at least one variant GSTP1 105 Val allele (p = 0.049) among men of African descent. We also observed a 2.1-fold increase in PCA risk associated with men possessing the GSTP1 (Val/Val) and GSTM1 (*1/*1 + *1/*0) alleles. MDR analysis validated these findings; detecting GSTP1 105 Val (p = 0.001) as the best single factor for predicting PCA risk. Our findings emphasize the importance of utilizing a combination of traditional and advanced statistical tools to identify and validate single gene and multi-locus interactions in relation to cancer susceptibility.
Project description:BACKGROUND: The association of the three Glutathione S-transferases (GSTs) polymorphisms (GSTM1, GSTT1 and GSTP1) genotypes with their individual susceptibilities to renal cell carcinoma (RCC) has not been well established. We performed a quantitative meta-analysis to assess the possible associations between the GSTM1, GSTT1 and GSTP1 genotypes and their individual susceptibilities to renal cell carcinoma. METHODS: We systematically searched the PubMed, CNKI and Embase databases to identify the relevant studies. Finally, 11 eligible studies were selected. The pooled odds ratios (ORs) with their 95% confidence intervals (CIs) were used to assess the association between the GSTs polymorphisms and the risk of RCC. Multiple subgroup analyses and quality assessment of the included studies were performed based on the available information. RESULTS: None of the GSTs polymorphisms had a significant association with the RCC risk. Similar results were found in the subgroup analyses, except for the GSTs polymorphisms in the situations described below. The GSTM1 and GSTT1 active genotypes in subjects exposed to pesticides (GSTM1: OR?=?3.44; 95% CI, 2.04-5.80; GSTT1: OR?=?2.84; 95% CI, 1.75-4.60), most of the GSTs genotypes in Asian populations (GSTT1: OR?=?2.39, 95% CI?=?1.63-3.51; GSTP1: Dominant model: OR?=?1.50, 95% CI?=?1.14-1.99; Additive model: OR?=?1.39, 95% CI?=?1.12-1.73; AG vs. AA: OR?=?1.47, 95% CI?=?1.10-1.97; GG vs. AA: OR?=?1.82, 95% CI?=?1.07-3.09) and the dual null genotype of GSTT1-GSTP1 (OR?=?2.84, 95% CI?=?1.75-4.60) showed positive associations with the RCC risk. CONCLUSION: Our present study provides evidence that the GSTM1, GSTT1 and GSTP1 polymorphisms are not associated with the development of RCC. However, more case-control studies are needed for further confirmation.
Project description:BACKGROUND: Progression of systemic lupus erythematosus (SLE) could be due to oxidative stress especially through reactive oxygen species (ROS). Detoxification of ROS is largely performed by Glutathione S-transferases (GSTs), therefore polymorphisms of GSTM1, GSTT1 and GSTP1 genes which decrease enzymes activity could affect SLE susceptibility. The aim of this study was to determine the effects of GSTM1 (deletion), GSTT1 (deletion) and GSTP1 (Ile105Val) polymorphisms on SLE susceptibility. METHODS: Genomic DNA was extracted from blood samples of 163 SLE patients and 180 age, sex and ethnically matched controls. GSTs genotypes were determined by polymerase chain reaction (PCR)-multiplex procedure or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: GSTT1 null genotype frequency was higher in SLE patients than controls. NO association observed between GSTM1 null genotype or GSTP1 Ile105Val polymorphism with SLE. Nevertheless combination of GSTT1 null/ GSTM1 null genotypes showed 2.8-fold increase in risk of SLE. Moreover the combination of GSTT1 null/ GSTM1 null/GSTP1 Ile/Val and Val/Val genotypes increased the SLE risk about 8 fold. CONCLUSION: Present data suggest that GSTT1 null/ GSTM1 null/GSTP1 Ile/Val and Val/Val genotypes might largely contribute to the pathogenesis of SLE.
Project description:BACKGROUND AND OBJECTIVES: The GSTM1, GSTT1 and GSTP1 polymorphisms might be involved in inactivation of procarcinogens that contribute to the genesis and progression of cancers. However, studies investigating the association between GSTM1, GSTT1 or GSTP1 polymorphisms and prostate cancer (PCa) risk report conflicting results, therefore, we conducted a meta-analysis to re-examine the controversy. METHODS: Published literature from PubMed, Embase, Google Scholar and China National Knowledge Infrastructure (CNKI) were searched (updated to June 2, 2012). According to our inclusion criteria, studies that observed the association between GSTM1, GSTT1 or GSTP1 polymorphisms and PCa risk were included. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of PCa associated with GSTM1, GSTT1 and GSTP1 polymorphisms. RESULTS: Fifty-seven studies involving 11313 cases and 12934 controls were recruited. The overall OR, which was 1.2854 (95% CI?=?1.1405-1.4487), revealed a significant risk of PCa and GSTM1 null genotype, and the similar results were observed when stratified by ethnicity and control source. Further, the more important is that the present study first reported the high risks of PCa for people who with dual null genotype of GSTM1 and GSTT1 (OR?=?1.4353, 95% CI?=?1.0345-1.9913), or who with GSTT1 null genotype and GSTP1 A131G polymorphism (OR?=?1.7335, 95% CI?=?1.1067-2.7152). But no association was determined between GSTT1 null genotype (OR?=?1.102, 95% CI?=?0.9596-1.2655) or GSTP1 A131G polymorphism (OR?=?1.0845, 95% CI?=?0.96-1.2251) and the PCa risk. CONCLUSIONS: Our meta-analysis suggested that the people with GSTM1 null genotype, with dual null genotype of GSTM1 and GSTT1, or with GSTT1 null genotype and GSTP1 A131G polymorphism are associated with high risks of PCa, but no association was found between GSTT1 null genotype or GSTP1 A131G polymorphism and the risk of PCa. Further rigorous analytical studies are highly expected to confirm our conclusions and assess gene-environment interactions with PCa risk.
Project description:BACKGROUND:Glutathione S-transferases (GSTs) polymorphisms may impact on chronic myeloid leukemia (CML) risk or heterogeneous responses to Imatinib mesylate (IM). The aim of this study was to evaluate the correlation between GSTs polymorphisms and CML risk, treatment response. METHODS:We genotyped GSTM1, GSTT1 null deletion polymorphisms, and GSTP1 Ile105Val polymorphism by PCR methods and BCR-ABL transcripts were analyzed by qRT-PCR in 104 CML patients and 104 sex- and age-matched healthy individuals. RESULTS:Individual analysis showed significant association of GSTM1 (p = 0.008; OR = 0.46; 95% CI: 0.26-0.82) and GSTP1 genes (p = 0.04; OR = 1.56; 95% CI: 1.016-2.423) with CML risk. The combined analysis indicated that GSTM1 null/GSTT1 present, GSTM1-null/GSTP1M*(AG/GG) as well as GSTT1 present/ GSTP1M* genotype were associated with CML risk (ORg(-):2.28; 95% CI: 1.29-4.04; ORgg: 2.85; 95% CI: 1.36-5.97; OR(-)g: 1.75; 95% CI: 0.99-3.06, respectively). The proportion of CML cancer attributable to the interaction of smoking and GSTM1 null, GSTT1null, and GSTP1 M* was 42%, 39%, and 13%, respectively. Patients with GSTM1-null and GSTP1 AG/GG genotype had significantly a lower rate of MMR achievement (p = 0.00; p = 0.009 respectively). Event-free survival (EFS) percentage was similar between GSTM1 null and GSTM1 present patients (p = 0.21). CONCLUSION:Our study suggests the influence of GSTM1 and GSTP1 polymorphisms on CML risk and treatment response. The interaction between GSTs polymorphisms and smoking plays a significant role on CML susceptibility.
Project description:BACKGROUND: Glutathione S transferase (GST) polymorphisms have been considered risk factors for the development of glaucoma, including primary open angle glaucoma (POAG) and other types of glaucoma. However, the results remain controversial. In this study, we have conducted a meta-analysis to assess the association between polymorphisms of GSTM1, GSTT1 and GSTP1 and glaucoma risk. METHODS: Published literature from PubMed and other databases were retrieved. All studies evaluating the association between GSTM1, GSTT1 and GSTP1 polymorphisms and glaucoma risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model. RESULTS: Twelve studies on GSTM1 (1109 cases and 844 controls), ten studies on GSTT1 (709 cases and 664 controls) and four studies on GSTP1 (543 cases and 511 controls) were included. By pooling all the studies, either GSTM1 or GSTT1 null polymorphism was not associated with a POAG risk, and this negative association maintained in Caucasian. The GSTP1 Ile 105 Val polymorphism was significantly correlated with increased POAG risk among Caucasian in a recessive model (Val/Val vs. Ile/Ile+Ile/Val: OR, 1.62, 95%CI: 1.00-2.61). Interestingly, increased glaucoma risk was associated with the combined GSTM1 and GSTT1 null genotypes (OR, 2.20; 95% CI, 1.47-3.31), and with the combined GSTM1 null and GSTP1 Val genotypes (OR, 1.86; 95% CI, 1.15-3.01). CONCLUSIONS: This meta-analysis suggests that combinations of GST polymorphisms are associated with glaucoma risk. Given the limited sample size, the associations between single GST polymorphism and glaucoma risk await further investigation.
Project description:The polymorphisms in genes including GSTM1, GSTP1 and GSTT1 have been found to predict development and therapeutic efficacy in various malignancies. Breast cancer is one of most common cancers among women. In this study, we evaluated the prognostic value of three functional polymorphisms of GSTs in patients with previously untreated metastatic breast cancer (MBC).The genotype of GSTT1, GSTP1, and GSTM1 in 170 patients with previously untreated MBC from one single center were assessed via PCR-based RFLP methods. The prognostic of polymorphisms on overall survival (OS) was examined using the Kaplan-Meier estimates and Cox proportional hazard ratio (HR) regression analyses.The null genotypes of GSTT1 and GSTM1 were significantly correlated to poor OS compared with the present genotypes, respectively. After adjusting for clinic-pathologic factors, GSTT1 and GSTM1 genetic variants were still significantly associated with OS (HR, 1.92; 95% CI, 1.26-2.91 and HR, 1.53; 95% CI, 1.05-2.23). GSTT1 and GSTM1 were independent survival predictors and GSTP1 was not associated with overall survival of previous untreated MBC.This exploratory analysis suggests that in addition to clinic-pathologic factors, the genetic variants in GSTT1 and GSTM1 might be predictive of survival outcome in patients with previously untreated MBC.
Project description:Polycyclic aromatic hydrocarbons (PAHs) may increase breast cancer risk, and the association may be modified by inherited differences in deactivation of PAH intermediates by glutathione S-transferases (GSTs). Few breast cancer studies have investigated the joint effects of multiple GSTs and a PAH biomarker.We estimated the breast cancer risk associated with multiple polymorphisms in the GST gene (GSTA1, GSTM1, GSTP1, and GSTT1) and the interaction with PAH-DNA adducts and cigarette smoking.We conducted unconditional logistic regression using data from a population-based sample of women (cases/controls, respectively): GST polymorphisms were genotyped using polymerase chain reaction and matrix-assisted laser desorption/ionization time-of-flight assays (n = 926 of 916), PAH-DNA adduct blood levels were measured by competitive enzyme-linked immunosorbent assay (n = 873 of 941), and smoking status was assessed by in-person questionnaires (n = 943 of 973).Odds ratios for joint effects on breast cancer risk among women with at least three variant alleles were 1.56 [95% confidence interval (CI), 1.13-2.16] for detectable PAH-DNA adducts and 0.93 (95% CI, 0.56-1.56) for no detectable adducts; corresponding odds ratios for three or more variants were 1.18 (95% CI, 0.82-1.69) for ever smokers and 1.44 (95% CI, 0.97-2.14) for never smokers. Neither interaction was statistically significant (p = 0.43 and 0.62, respectively).We found little statistical evidence that PAHs interacted with GSTT1, GSTM1, GSTP1, and GSTA1 polymorphisms to further increase breast cancer risk.
Project description:The inclusion of genotype at Acute Lymphoblastic Leukemia (ALL) diagnosis as a genetic predictor of disease outcome is under constant study. However, results are inconclusive and seem to be population specific. We analyzed the predictive value of germline polymorphisms for childhood ALL relapse and survival. We retrospectively recruited 140 Argentine patients with de novo ALL. Genotypes were analyzed using PCR-RFLP (GSTP1 c.313A > G, MDR1 c.3435T > C, and MTHFR c.665C > T) and multiplex PCR (GSTT1 null, GSTM1 null). Patients with the GSTP1 c.313GG genotype had an increased risk for relapse in univariate (OR = 2.65, 95% CI = 1.03-6.82, p = 0.04) and multivariate (OR = 3.22, 95% CI = 1.17-8.83, p = 0.02) models. The combined genotype slightly increased risk for relapse in the univariate (OR = 2.82, 95% CI = 1.09-7.32, p = 0.03) and multivariate (OR = 2.98, 95% CI = 1.14-7.79, p = 0.03) models for patients with 2/3-risk-genotypes (GSTT1 null, GSTM1 null, GSTP1 c.313GG). The Recurrence-Free Survival (RFS) was shorter for GSTP1 c.313GG (p = 0.025) and 2/3-risk-genotypes (p = 0.021). GST polymorphisms increased the risk of relapse and RFS of patients with childhood ALL. The inclusion of these genetic markers in ALL treatment protocols might improve risk stratification and reduce the number of relapses and deaths.
Project description:The aim of this study was to evaluate specific glutathione S-transferase (GST) gene variants as determinants of risk in patients with clear cell renal cell carcinoma (cRCC), independently or simultaneously with established RCC risk factors, as well as to discern whether phenotype changes reflect genotype-associated risk. GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 cRCC patients and 274 matched controls. Benzo(a)pyrene diolepoxide (BPDE)-DNA adducts were determined in DNA samples obtained from cRCC patients by ELISA method. Significant association between GST genotype and risk of cRCC development was found for the GSTM1-null and GSTP1-variant genotype (p = 0.02 and p<0.001, respectively). Furthermore, 22% of all recruited cRCC patients were carriers of combined GSTM1-null, GSTT1-active, GSTA1-low activity and GSTP1-variant genotype, exhibiting 9.32-fold elevated cRCC risk compared to the reference genotype combination (p = 0.04). Significant association between GST genotype and cRCC risk in smokers was found only for the GSTP1 genotype, while GSTM1-null/GSTP1-variant/GSTA1 low-activity genotype combination was present in 94% of smokers with cRCC, increasing the risk of cRCC up to 7.57 (p = 0.02). Furthermore, cRCC smokers with GSTM1-null genotype had significantly higher concentration of BPDE-DNA adducts in comparison with GSTM1-active cRCC smokers (p = 0.05). GSTM1, GSTT1, GSTA1 and GSTP1 polymorphisms might be associated with the risk of cRCC, with special emphasis on GSTM1-null and GSTP1-variant genotypes. Combined GSTM1-null, GSTT1-active, GSTA1 low activity and GSTP1-variant genotypes might be considered as "risk-carrying genotype combination" in cRCC.