Gene Summary

Gene:GSTM3; glutathione S-transferase mu 3
Aliases: GST5, GSTB, GTM3, GSTM3-3
Summary:Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Mutations of this class mu gene have been linked with a slight increase in a number of cancers, likely due to exposure with environmental toxins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:glutathione S-transferase Mu 3
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

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Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: GSTM3 (cancer-related)

Moghimi M, Sobhan MR, Jarahzadeh MH, et al.
Association of GSTM1, GSTT1, GSTM3, and GSTP1 Genes Polymorphisms with Susceptibility to Osteosarcoma: a Case- Control Study and Meta-Analysis
Asian Pac J Cancer Prev. 2019; 20(3):675-682 [PubMed] Related Publications
Background: Some studies have investigated the association of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with susceptibility to osteosarcoma; however, these studies results are inconsistent and inconclusive. In order to drive a more precise estimation, the present case-control study and meta-analysis was performed to investigate association of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with osteosarcoma. Methods: Eligible articles were identified by a search of several electronic databases for the period up to May 5, 2018. Odds ratios were pooled using either fixed-effects or random effects models. Results: Finally, a total of 24 case-control studies with 2,405 osteosarcoma cases and 3,293 controls were included in the present meta-analysis. Overall, significantly increased osteosarcoma risk was found when all studies were pooled into the meta-analysis of GSTT1 (Null vs. Present: OR= 1.247 95% 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). In the stratified, significantly increased osteosarcoma risk was observed for GSTT1 polymorphism among Asians (Null vs. Present: OR= 1.300 95% CI 1.034-1.635, P= 0.025), but not among Caucasians. Conclusions: This meta-analysis demonstrated that GSTP1 and GSTT1 null genotype are associated with the risk of osteosarcoma. Future large welldesigned epidemiological studies are warranted to validate our results.

Lin JH, Tu SH, Chen LC, et al.
Oestrogen receptor-regulated glutathione S-transferase mu 3 expression attenuates hydrogen peroxide-induced cytotoxicity, which confers tamoxifen resistance on breast cancer cells.
Breast Cancer Res Treat. 2018; 172(1):45-59 [PubMed] Related Publications
PURPOSE: Glutathione S-transferase mu 3 (GSTM3) is an enzyme involving in the detoxification of electrophilic compounds by conjugation with glutathione. Higher GSTM3 mRNA levels were reported in patients with ERα-positive breast cancer who received only tamoxifen therapy after surgery. Thus, this study aimed to clarify the oncogenic characteristics of GSTM3 in breast cancer and the mechanism of tamoxifen resistance.
METHODS: GSTM3 expression in human breast tumour tissues (n = 227) was analysed by RT-PCR and quantitative PCR. Western blot, promoter activity assays, and chromatin immunoprecipitation (ChIP) assays were used to investigate the mechanism of GSTM3 gene regulation. Hydrogen peroxide (H
RESULTS: GSTM3 mRNA was highly expressed in ER- and HER2-positive breast cancers. Moreover, patients who received adjuvant Herceptin had increased GSTM3 mRNA levels in tumour tissue. Oestrogen-activated GSTM3 gene expression through ERα-mediated recruitment of SP1, EP300, and AP-1 complexes. GSTM3-silenced MCF-7 cells were more sensitive to H
CONCLUSIONS: ROS production is one mechanism by which cancer drugs kill tumour cells, and according to our evidence, GSTM3 may play an important role in preventing breast cancer treatment-induced cellular cytotoxicity.

Shiota M, Fujimoto N, Itsumi M, et al.
Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress.
Ann Oncol. 2017; 28(3):569-575 [PubMed] Related Publications
Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). This study investigated the association between genetic variations in antioxidant enzymes and the efficacy of ADT as well as its biological background.
Patients and methods: The non-synonymous or promoter-locating polymorphisms of antioxidant enzymes were examined as well as the time to CRPC progression and overall survival in 104 and 92 patients treated with ADT for metastatic and non-metastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells.
Results: In metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 and CT/TT allele in CAT rs564250 were associated with a significantly lower risk of progression to CRPC and all-cause death compared with homozygotes of the major AA allele (hazard ratio [HR]; [95% confidence interval (CI)], 0.55 [0.34-0.86], P = 0.0086) and CC allele (HR; [95% CI], 0.48 [0.24-0.88], P = 0.016), respectively. On multivariate analyses, only GSTM3 rs7483 was associated with significant progression risk (AG/GG versus AA; HR; [95% CI], 0.45 [0.25-0.79], P = 0.0047) even after Bonferroni adjustment. In non-metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 was associated with a significantly lower risk of progression to CRPC (HR; [95% CI], 0.35 [0.10-0.93], P = 0.034) and all-cause death (HR; [95% CI], 0.26 [0.041-0.96], P = 0.043) compared with the AA allele. Intracellular reactive oxygen species levels were increased, accompanied with augmented GSTM3 expression in both castration-resistant and enzalutamide-resistant cells.
Conclusions: Differential activity of antioxidant enzymes caused by the polymorphism in GSTM3 may contribute to resistance to hormonal therapy through oxidative stress. The GSTM3 rs7483 polymorphism may be a promising biomarker for prostate cancer patients treated with ADT.

Bracalente C, Ibañez IL, Berenstein A, et al.
Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Upregulation of antioxidant genes correlates with regression of melanoma malignancy and with malignant progression when downregulated.
Oncotarget. 2016; 7(27):41154-41171 [PubMed] Free Access to Full Article Related Publications
Reactive oxygen species (ROS) are implicated in tumor transformation. The antioxidant system (AOS) protects cells from ROS damage. However, it is also hijacked by cancers cells to proliferate within the tumor. Thus, identifying proteins altered by redox imbalance in cancer cells is an attractive prognostic and therapeutic tool. Gene expression microarrays in A375 melanoma cells with different ROS levels after overexpressing catalase were performed. Dissimilar phenotypes by differential compensation to hydrogen peroxide scavenging were generated. The melanotic A375-A7 (A7) upregulated TYRP1, CNTN1 and UCHL1 promoting melanogenesis. The metastatic A375-G10 (G10) downregulated MTSS1 and TIAM1, proteins absent in metastasis. Moreover, differential coexpression of AOS genes (EPHX2, GSTM3, MGST1, MSRA, TXNRD3, MGST3 and GSR) was found in A7 and G10. Their increase in A7 improved its AOS ability and therefore, oxidative stress response, resembling less aggressive tumor cells. Meanwhile, their decrease in G10 revealed a disruption in the AOS and therefore, enhanced its metastatic capacity.These gene signatures, not only bring new insights into the physiopathology of melanoma, but also could be relevant in clinical prognostic to classify between non aggressive and metastatic melanomas.

Aşık E, Aslan TN, Volkan M, Güray NT
2-Amino-2-deoxy-glucose conjugated cobalt ferrite magnetic nanoparticle (2DG-MNP) as a targeting agent for breast cancer cells.
Environ Toxicol Pharmacol. 2016; 41:272-8 [PubMed] Related Publications
In this study, 2-amino-2-deoxy-glucose (2DG) was conjugated to COOH modified cobalt ferrite magnetic nanoparticles (COOH-MNPs), which were designed to target tumor cells as a potential targetable drug/gene delivery agent for cancer treatment. According to our results, it is apparent that, 2DG labeled MNPs were internalized more efficiently than COOH-MNPs under the same conditions in all cell types (MDA-MB-231 and MCF-7 cancer and MCF-10A normal breast cells) (p<0.001). Moreover, the highest amount of uptake was observed in MDA-MB-231, followed by MCF-7 and normal MCF-10A cells for both MNPs. The apoptotic effects of 2DG-MNPs were further evaluated, and it was found that apoptosis was not induced at low concentrations of 2DG-MNPs in all cell types, whereas dramatic cell death was observed at higher concentrations. In addition, the gene expression levels of four drug-metabolizing enzymes, two Phase I (CYP1A1, CYP1B1) and two Phase II (GSTM3, GSTZ1) were also increased with the high concentrations of 2DG-MNPs.

Stavrinou P, Mavrogiorgou MC, Polyzoidis K, et al.
Expression Profile of Genes Related to Drug Metabolism in Human Brain Tumors.
PLoS One. 2015; 10(11):e0143285 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Endogenous and exogenous compounds as well as carcinogens are metabolized and detoxified by phase I and II enzymes, the activity of which could be crucial to the inactivation and hence susceptibility to carcinogenic factors. The expression of these enzymes in human brain tumor tissue has not been investigated sufficiently. We studied the association between tumor pathology and the expression profile of seven phase I and II drug metabolizing genes (CYP1A1, CYP1B1, ALDH3A1, AOX1, GSTP1, GSTT1 and GSTM3) and some of their proteins.
METHODS: Using qRT-PCR and western blotting analysis the gene and protein expression in a cohort of 77 tumors were investigated. The major tumor subtypes were meningioma, astrocytoma and brain metastases, -the later all adenocarcinomas from a lung primary.
RESULTS: Meningeal tumors showed higher expression levels for AOX1, CYP1B1, GSTM3 and GSTP1. For AOX1, GSTM and GSTP1 this could be verified on a protein level as well. A negative correlation between the WHO degree of malignancy and the strength of expression was identified on both transcriptional and translational level for AOX1, GSTM3 and GSTP1, although the results could have been biased by the prevalence of meningiomas and glioblastomas in the inevitably bipolar distribution of the WHO grades. A correlation between the gene expression and the protein product was observed for AOX1, GSTP1 and GSTM3 in astrocytomas.
CONCLUSIONS: The various CNS tumors show different patterns of drug metabolizing gene expression. Our results suggest that the most important factor governing the expression of these enzymes is the histological subtype and to a far lesser extent the degree of malignancy itself.

Wang SM, Sun ZQ, Li HY, et al.
Temporal Identification of Dysregulated Genes and Pathways in Clear Cell Renal Cell Carcinoma Based on Systematic Tracking of Disrupted Modules.
Comput Math Methods Med. 2015; 2015:313740 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The objective of this work is to identify dysregulated genes and pathways of ccRCC temporally according to systematic tracking of the dysregulated modules of reweighted Protein-Protein Interaction (PPI) networks.
METHODS: Firstly, normal and ccRCC PPI network were inferred and reweighted based on Pearson correlation coefficient (PCC). Then, we identified altered modules using maximum weight bipartite matching and ranked them in nonincreasing order. Finally, gene compositions of altered modules were analyzed, and pathways enrichment analyses of genes in altered modules were carried out based on Expression Analysis Systematic Explored (EASE) test.
RESULTS: We obtained 136, 576, 693, and 531 disrupted modules of ccRCC stages I, II, III, and IV, respectively. Gene composition analyses of altered modules revealed that there were 56 common genes (such as MAPK1, CCNA2, and GSTM3) existing in the four stages. Besides pathway enrichment analysis identified 5 common pathways (glutathione metabolism, cell cycle, alanine, aspartate, and glutamate metabolism, arginine and proline metabolism, and metabolism of xenobiotics by cytochrome P450) across stages I, II, III, and IV.
CONCLUSIONS: We successfully identified dysregulated genes and pathways of ccRCC in different stages, and these might be potential biological markers and processes for treatment and etiology mechanism in ccRCC.

Jaramillo-Rangel G, Ortega-Martínez M, Cerda-Flores RM, Barrera-Saldaña HA
Polymorphisms in GSTM1, GSTT1, GSTP1, and GSTM3 genes and breast cancer risk in northeastern Mexico.
Genet Mol Res. 2015; 14(2):6465-71 [PubMed] Related Publications
Glutathione S-transferases (GSTs) are a family of phase II metabolizing enzymes involved in carcinogen detoxification and the metabolism of various bioactive compounds. Several genes that code for these enzymes are polymorphic in an ethnicity-dependent manner, with particular genotypes previously associated with an increased risk of breast cancer. The purpose of this study was to determine the frequencies of polymorphisms in the genes GSTM1, GSTT1, GSTP1, and GSTM3 and to investigate whether an association exists between these genes and breast cancer risk in subjects from northeastern Mexico. Genotypes were determined for 243 women with histologically confirmed breast cancer and 118 control subjects. Gene polymorphisms were analyzed using a DNA microarray. We found an increased breast cancer risk associated with the GSTM1 gene deletion polymorphism (OR = 2.19; 95%CI = 1.50-3.21; P = 0.001). No associations between the GSTT1, GSTP1, and GSTM3 genotypes and neoplasia risk were observed. In conclusion, we determined the genotype distribution of GST polymorphisms in control subjects and breast cancer patients from northeastern Mexico. The GSTM1 null genotype was associated with breast cancer risk. Our findings may be used to individualize breast cancer screening and therapeutic intervention in our population, which displays ethnic characteristics that differentiate it from other populations in Mexico.

Qu K, Liu SS, Wang ZX, et al.
Polymorphisms of glutathione S-transferase genes and survival of resected hepatocellular carcinoma patients.
World J Gastroenterol. 2015; 21(14):4310-22 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the effects of single nucleotide polymorphisms (SNPs) in glutathione S-transferase (GST) genes on survival of hepatocellular carcinoma (HCC) patients.
METHODS: Twelve tagging SNPs in GST genes (including GSTA1, GSTA4, GSTM2, GSTM3, GSTO1, GSTO2 and GSTP1) were genotyped using Sequenom MassARRAY iPLEX genotyping method in a cohort of 214 Chinese patients with resected HCC. The Cox proportional hazards model and log-rank test were performed to determine the SNPs related to outcome. Additionally, stratified analysis was performed at each level of the demographic and clinical variables. An SNP-gene expression association model was further established to investigate the correlation between SNP and gene expression.
RESULTS: Two SNPs (GSTO2: rs7085725 and GSTP1: rs4147581) were significantly associated with overall survival in HCC patients (P = 0.035 and 0.042, respectively). In stratified analysis, they were more significantly associated with overall survival in patients with younger age, male gender and cirrhosis. We further investigated cumulative effects of these two SNPs on overall survival in HCC patients. Compared with the patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 1.70-fold increased risk of death (P < 0.001). The cumulative effects were more significant in those patients with younger age, male gender and cirrhosis (HR = 2.00, 1.94 and 1.97, respectively; all P < 0.001). Additionally, we found that heavy smoking resulted in a significantly worse overall survival in those patients carrying variant alleles of rs7085725 (HR = 2.07, 95%CI: 1.13-3.76, P = 0.018). The distributions of GSTO2: rs7085725 and GSTP1: rs4147581 genotypes were associated with altered gene expression and contributed to influences on overall survival.
CONCLUSION: Our study provides the first evidence that GSTO2 and GSTP1 gene polymorphisms may serve as independent prognostic markers for HCC patients.

Gross-Davis CA, Heavner K, Frank AL, et al.
The role of genotypes that modify the toxicity of chemical mutagens in the risk for myeloproliferative neoplasms.
Int J Environ Res Public Health. 2015; 12(3):2465-85 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation--JAK2 V617F--suggesting a potential role for environmental mutagens.
METHODS: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921-1968 and residing in the area between 2000-2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease.
RESULTS: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3-5 fold increased risk.
CONCLUSIONS: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs.

Jiang XY, Chang FH, Bai TY, et al.
Susceptibility of lung cancer with polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 genotypes in the population of Inner Mongolia region.
Asian Pac J Cancer Prev. 2014; 15(13):5207-14 [PubMed] Related Publications
BACKGROUND: To study the relationship of susceptibility to lung cancer with the gene polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1, GSTP1 and smoking status in Han and Mongolian populations of Inner Mongolia, an autonomous region of China.
MATERIALS AND METHODS: PCR-RFLP, allele-specific and multiplex PCR were employed to identify the genotypes of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 in a case-control study of 322 lung cancer patients diagnosed by bronchoscopy and 456 controls free of malignancy.
RESULTS: There is a significant difference in genotypic frequency of GSTT1 of healthy Mongolian and Han subjects. A statistically prominent association was found between CYP1A1 Msp1 (vt/vt) (OR=4.055, 95%CI:2.107-7.578, p=0.000), GSTM1 (-) (OR=2.290, 95%CI:1.467-3.573, p=0.000) and lung cancer in Mongolians. Similarly, in the Han population, CYP1A1 Msp1 (vt/vt) (OR=3.194, 95%CI:1.893-5.390, p=0.000) and GSTM1 (-) (OR=1.884, 95%CI:1.284-2.762, p=0.001) carriers also had an elevated risk of lung cancer. The smokers were more susceptible to lung cancer 2.144 fold and 1.631 fold than non-smokers in Mongolian and Han populations, respectively. The smokers who carried with CYP1A1 Msp1 (wt/vt+vt/vt), exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) respectively were found all to have a high risk of lung cancer.
CONCLUSIONS: CYP1A1 Msp1 (vt/ vt) and GSTM1 (-) are risk factors of lung cancer in Han and Mongolian population in the Inner Mongolia region. The smokers with CYP1A1 Msp1 (wt/vt+vt/vt), CYP1A1 exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) genotypes, respectively, are at elevated risk of lung cancer.

Tan X, Wang Y, Han Y, et al.
Genetic variation in the GSTM3 promoter confer risk and prognosis of renal cell carcinoma by reducing gene expression.
Br J Cancer. 2013; 109(12):3105-15 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glutathione S-transferase mu 3 (GSTM3) has been proven to be downregulated in renal cell carcinoma (RCC). We aimed to characterise the role of GSTM3 and its genetic predisposition on the occurrence and postoperative prognosis of RCC.
METHODS: The effect of GSTM3 on RCC aggressiveness was examined using transfection and silencing methods. Glutathione S-transferase mu 3 expression in renal tissues was examined by immunohistochemistry. The associations of rs1332018 (A-63C) and rs7483 (V224I) polymorphisms with RCC risk were examined using 400 RCC patients and 802 healthy controls. The factors contributing to postoperative disease-specific survival of RCC patients were evaluated using the Cox proportional hazard model.
RESULTS: Glutathione S-transferase mu 3 silencing increased the invasion and anchorage-independent growth of RCC cell lines. rs1332018 (AC+CC vs AA), which correlated with low expression of GSTM3 in kidney, was associated with RCC risk (odds ratio, 1.446; 95% confidence interval (CI), 1.111-1.882). rs1332018 variants and low GSTM3 expression significantly predicted unfavourable postoperative survivals of RCC patients (P<0.05). rs1332018 variants independently predicted a poor prognosis (hazard ratio, 2.119; 95% CI, 1.043-4.307).
CONCLUSION: Glutathione S-transferase mu 3 may function as a tumour suppressor in RCC. rs1332018 genetic variants predispose the host to downregulating GSTM3 expression in kidney, facilitate carcinogenesis, and predict an unfavourable postoperative prognosis of RCC.

Rumiato E, Boldrin E, Amadori A, Saggioro D
DMET™ (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity.
Cancer Chemother Pharmacol. 2013; 72(2):483-8 [PubMed] Related Publications
PURPOSE: 5-fluorouracil (5-FU) has been widely used since the 1980s, and it remains the backbone of many chemotherapeutic combination regimens. However, its use is often limited by the occurrence of severe toxicity. Although several reports have shown the detrimental effect of some dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS) gene polymorphisms in patients undergoing 5-FU-based treatment, they account for only a minority of toxicities.
METHODS: Looking for new candidate genetic variants associated with 5-FU-induced toxicity, we used the innovative genotyping microarray Affymetrix Drug-Metabolizing Enzymes and Transporters (DMET)™ Plus GeneChip that interrogates 1,936 genetic variants distributed in 231 genes involved in drug metabolism, excretion, and transport. To reduce variability, we analyzed samples from colorectal cancer patients who underwent fairly homogenous treatments (i.e., Machover or Folfox) and experienced G3 or G4 toxicity; control patients were matched for therapy and selected from those who did not disclose toxicity (G0-G1).
RESULTS: Pharmacogenetic genotyping showed no significant difference in DPYD and TYMS genetic variants distribution between cases and controls. However, other polymorphisms could account for 5-FU-induced toxicity, with the CHST1 rs9787901 and GSTM3 rs1799735 having the strongest association.
CONCLUSIONS: Although exploratory, this study suggests that genetic polymorphisms not directly related to 5-FU pharmacokinetics and pharmacodynamics are involved in 5-FU-induced toxicity. Our data also indicates DMET™ microarray as a valid approach to discover new genetic determinants influencing chemotherapy-induced toxicity.

Feng X, Dong CQ, Shi JJ, et al.
Lack of association of glutathione S-transferase M3 gene polymorphism with the susceptibility of lung cancer.
Asian Pac J Cancer Prev. 2012; 13(9):4465-8 [PubMed] Related Publications
OBJECTIVE: The conclusions of published reports on the relationship between the glutathione S-transferase M3 (GSTM3) A/B gene polymorphism and the risk of lung cancer are still debated. This meta-analysis was performed to evaluate the association between GSTM3 and the risk of lung cancer.
METHODS: Association investigations were identified from PubMed, Embase, and Cochrane Library, and eligible studies were included and synthesized using a meta-analysis method.
RESULTS: Eight reports were included into this meta-analysis for the association of GSTM3 A/B gene polymorphism and lung cancer susceptibility, covering 1,854 patients with lung cancer and 1,926 controls. No association between the GSTM3 A/B gene polymorphism and lung cancer was found in this meta-analysis (B allele: OR = 1.25, 95% CI: 0.89-1.76, P = 0.20; BB genotype: OR = 1.53, 95% CI: 0.71-3.32, P = 0.28; AA genotype: OR = 0.85, 95% CI: 0.59-1.23, P = 0.39).
CONCLUSIONS: The GSTM3 A/B gene polymorphism is not associated with lung cancer susceptibility. However, more studies on the relationship between GSTM3 A/B gene polymorphism and the risk of lung cancer should be performed in the future.

Ruder AM, Yiin JH, Waters MA, et al.
The Upper Midwest Health Study: gliomas and occupational exposure to chlorinated solvents.
Occup Environ Med. 2013; 70(2):73-80 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: Occupational exposure to chlorinated aliphatic solvents has been associated with an increased cancer risk, including brain cancer. However, many of these solvents remain in active, large-volume use. We evaluated glioma risk from non-farm occupational exposure (ever/never and estimated cumulative exposure) to any of the six chlorinated solvents--carbon tetrachloride, chloroform, methylene chloride, trichloroethylene, tetrachloroethylene or 1,1,1--trichloroethane-among 798 cases and 1175 population-based controls, aged 18-80 years and non-metropolitan residents of Iowa, Michigan, Minnesota and Wisconsin. Methods Solvent use was estimated based on occupation, industry and era, using a bibliographic database of published exposure levels and exposure determinants. Unconditional logistic regression was used to calculate ORs adjusted for frequency matching variables age group and sex, and age and education. Additional analyses were limited to 904 participants who donated blood specimens (excluding controls reporting a previous diagnosis of cancer) genotyped for glutathione-S-transferases GSTP1, GSTM3 and GSTT1. Individuals with functional GST genes might convert chlorinated solvents crossing the blood-brain barrier into cytotoxic metabolites.
RESULTS: Both estimated cumulative exposure (ppm-years) and ever exposure to chlorinated solvents were associated with decreased glioma risk and were statistically significant overall and for women. In analyses comparing participants with a high probability of exposure with the unexposed, no associations were statistically significant. Solvent-exposed participants with functional GST genes were not at increased risk of glioma.
CONCLUSIONS: We observed no associations of glioma risk and chlorinated solvent exposure. Large pooled studies are needed to explore the interaction of genetic pathways and environmental and occupational exposures in glioma aetiology.

Gilsing AM, Berndt SI, Ruder EH, et al.
Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer.
Carcinogenesis. 2012; 33(7):1332-9 [PubMed] Free Access to Full Article Related Publications
Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P(interaction) = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11-1.85, P(trend) = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30-0.84, P(trend) = 0.01). In addition, we observed some suggestive (P < 0.05) modifying effects for SNPs in other XME genes (UGT1A, CYP2E1, EPHX1, AHR and GSTM3), but these were not significant after adjustment for multiple testing. This large and comprehensive study of XME genes, meat mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.

Searles Nielsen S, Mueller BA, Preston-Martin S, et al.
Childhood brain tumors and maternal cured meat consumption in pregnancy: differential effect by glutathione S-transferases.
Cancer Epidemiol Biomarkers Prev. 2011; 20(11):2413-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Some epidemiologic studies suggest that maternal consumption of cured meat during pregnancy may increase risk of brain tumors in offspring. We explored whether this possible association was modified by fetal genetic polymorphisms in genes coding for glutathione S-transferases (GSTs) that may inactivate nitroso compounds.
METHODS: We assessed six GST variants: GSTM1 null, GSTT1 null, GSTP1(I105V) (rs1695), GSTP1(A114V) (rs1138272), GSTM3*B (3-bp deletion), and GSTM3(A-63C) (rs1332018) within a population-based case-control study with data on maternal prenatal cured meat consumption (202 cases and 286 controls born in California or Washington, 1978-1990).
RESULTS: Risk of childhood brain tumor increased with increasing cured meat intake by the mother during pregnancy among children without GSTT1 [OR = 1.29; 95% confidence interval (95% CI), 1.07-1.57 for each increase in the frequency of consumption per week] or with potentially reduced GSTM3 (any -63C allele; OR = 1.14; 95% CI, 1.03-1.26), whereas no increased risk was observed among those with GSTT1 or presumably normal GSTM3 levels (interaction P = 0.01 for each).
CONCLUSIONS: Fetal ability to deactivate nitrosoureas may modify the association between childhood brain tumors and maternal prenatal consumption of cured meats.
IMPACT: These results support the hypothesis that maternal avoidance during pregnancy of sources of some nitroso compounds or their precursors may reduce risk of brain tumors in some children.

Cabello CM, Lamore SD, Bair WB, et al.
DCPIP (2,6-dichlorophenolindophenol) as a genotype-directed redox chemotherapeutic targeting NQO1*2 breast carcinoma.
Free Radic Res. 2011; 45(3):276-92 [PubMed] Free Access to Full Article Related Publications
Accumulative experimental evidence suggests feasibility of chemotherapeutic intervention targeting human cancer cells by pharmacological modulation of cellular oxidative stress. Current efforts aim at personalization of redox chemotherapy through identification of predictive tumour genotypes and redox biomarkers. Based on earlier research demonstrating that anti-melanoma activity of the pro-oxidant 2,6-dichlorophenolindophenol (DCPIP) is antagonized by cellular NAD(P)H:quinone oxidoreductase (NQO1) expression, this study tested DCPIP as a genotype-directed redox chemotherapeutic targeting homozygous NQO1*2 breast carcinoma, a common missense genotype [rs1800566 polymorphism; NP_000894.1:p.Pro187Ser] encoding a functionally impaired NQO1 protein. In a panel of cultured breast carcinoma cell lines and NQO1-transfectants with differential NQO1 expression levels, homozygous NQO1*2 MDA-MB231 cells were hypersensitive to DCPIP-induced caspase-independent cell death that occurred after early onset of oxidative stress with glutathione depletion and loss of genomic integrity. Array analysis revealed upregulated expression of oxidative (GSTM3, HMOX1, EGR1), heat shock (HSPA6, HSPA1A, CRYAB) and genotoxic stress response (GADD45A, CDKN1A) genes confirmed by immunoblot detection of HO-1, Hsp70, Hsp70B', p21 and phospho-p53 (Ser15). In a murine xenograft model of human homozygous NQO1*2-breast carcinoma, systemic administration of DCPIP displayed significant anti-tumour activity, suggesting feasibility of redox chemotherapeutic intervention targeting the NQO1*2 genotype.

Malik MA, Upadhyay R, Mittal RD, et al.
Association of xenobiotic metabolizing enzymes genetic polymorphisms with esophageal cancer in Kashmir Valley and influence of environmental factors.
Nutr Cancer. 2010; 62(6):734-42 [PubMed] Related Publications
The Kashmir Valley has an elevated incidence rate of esophageal cancer (EC). Several environmental and genetic factors have been suspected for development of EC. A case-control study was performed in 135 EC patients and 195 healthy controls to analyze association of polymorphisms in glutathione S-transferase (GST) mu (GSTM1), GST theta (GSTT1), GST pi (GSTP1), GSTM3, Cytochrome P450 (CYP)1A1, and CYP2E1 genes with susceptibility to EC as well as their interaction with environmental factors such as smoking and high consumption of salted tea in Kashmir valley. All subjects were genotyped through polymerase chain reaction restriction fragment length polymorphism. Data was statistically analyzed using the chi-square test and logistic regression model. Results showed that GSTP1313 val/val and CYP2E1c1c2 genotypes imparted risk for esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma [EADC; odds ratio (OR) = 3.24, 95% confidence interval (CI) = 1.30-8.05; OR = 4.20, 95% CI = 1.65-10.70], respectively. GSTM3AB genotype/B allele was found to be associated with low risk for EC. Tobacco smoking through hukka (water pipe) and consumption of salted tea itself were high risk factors for developing EC (OR = 21.44, 95% CI = 11.63-39.54; OR = 14.86, 95% CI = 8.41-26.24), and the risks were modulated through the interaction of GSTM3AB, GSTP1val/val genotypes. In conclusion, GSTP1val/val and CYP2E1c1c2 genotypes/c2 allele increased the risk of ESCC and EADC, respectively, in the Kashmiri population; whereas GSTM3AB genotype imparted lower risk for both ESCC and EADC.

Salinas-Souza C, Petrilli AS, de Toledo SR
Glutathione S-transferase polymorphisms in osteosarcoma patients.
Pharmacogenet Genomics. 2010; 20(8):507-15 [PubMed] Related Publications
BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children and adolescents. Multidrug resistance and poor clinical outcome are the problems that still affect osteosarcoma patients. The glutathione S-transferase supergene family includes several genes that encode enzymes involved in the detoxification of many xenobiotic agents, including carcinogens and anticancer drugs. The polymorphisms in these genes have already been associated both with cancer susceptibility and anticancer drugs resistance.
OBJECTIVES: This study aims to investigate the genotype frequencies of GSTM1, GSTT1 and GSTM3 genes in 80 osteosarcoma patients and 160 normal control participants, and also the influence of these polymorphisms in the clinical outcome of osteosarcoma patients.
METHODS: GSTM1 and GSTT1 deletion polymorphisms were examined through a multiplex-PCR and the GSTM3 polymorphism of three base pair-deletion at intron 6 using PCR-restriction fragments length polymorphism method.
RESULTS: We found that GSTM1 null genotype is correlated to poor clinical outcome characterized by the increased lung relapse occurrence [odds ratio (OR)=2.71, P=0.036], while the presence of at least one GSTM1 allele is associated with a good response to treatment and better survival (OR=4.28, P=0.020 and hazards ratio=4.09, P=0.0078, respectively). The GSTT1 null genotype was correlated with a better overall survival (hazards ratio=7.15, P=0.0247), whereas GSTM3*B allele was associated with metastasis at diagnosis (OR=2.83, P=0.028).
CONCLUSION: The findings of this study suggest that GST polymorphisms may have a role in treatment response and osteosarcoma progression.

Quiles-Perez R, Muñoz-Gámez JA, Ruiz-Extremera A, et al.
Inhibition of poly adenosine diphosphate-ribose polymerase decreases hepatocellular carcinoma growth by modulation of tumor-related gene expression.
Hepatology. 2010; 51(1):255-66 [PubMed] Related Publications
UNLABELLED: Hepatocellular carcinoma (HCC) is associated with a poor prognosis due to a lack of effective treatment options. In HCC a significant role is played by DNA damage and the inflammatory response. Poly (ADP-ribose) polymerase-1 (PARP-1) is an important protein that regulates both these mechanisms. The objective of this study was to examine the effect of pharmacology PARP-1 inhibition on the reduction of tumor volume of HCC xenograft and on the hepatocarcinogenesis induced by diethyl-nitrosamine (DEN). Pharmacologic PARP-1 inhibition with DPQ greatly reduces tumor xenograft volume with regard to a nontreated xenograft (394 mm(3) versus 2,942 mm(3), P < 0.05). This observation was paralleled by reductions in xenograft mitosis (P = 0.02) and tumor vasculogenesis (P = 0.007, confirmed by in vitro angiogenesis study), as well as by an increase in the number of apoptotic cells in DPQ-treated mice (P = 0.04). A substantial difference in key tumor-related gene expression (transformed 3T3 cell double minute 2 [MDM2], FLT1 [vascular endothelial growth factor receptor-1, VEGFR1], epidermal growth factor receptor [EPAS1]/hypoxia-inducible factor 2 [HIF2A], EGLN1 [PHD2], epidermal growth factor receptor [EGFR], MYC, JUND, SPP1 [OPN], hepatocyte growth factor [HGF]) was found between the control tumor xenografts and the PARP inhibitor-treated xenografts (data confirmed in HCC cell lines using PARP inhibitors and PARP-1 small interfering RNA [siRNA]). Furthermore, the results obtained in mice treated with DEN to induce hepatocarcinogenesis showed, after treatment with a PARP inhibitor (DPQ), a significant reduction both in preneoplastic foci and in the expression of preneoplastic markers and proinflammatory genes (Gstm3, Vegf, Spp1 [Opn], IL6, IL1b, and Tnf), bromodeoxyuridine incorporation, and NF-kappaB activation in the initial steps of carcinogenesis (P < 0.05).
CONCLUSION: This study shows that PARP inhibition is capable of controlling HCC growth and preventing tumor vasculogenesis by regulating the activation of different genes involved in tumor progression.

Chatzimichalis M, Xenellis J, Tzagaroulakis A, et al.
GSTT1, GSTM1, GSTM3 and NAT2 polymorphisms in laryngeal squamous cell carcinoma in a Greek population.
J Laryngol Otol. 2010; 124(3):318-23 [PubMed] Related Publications
OBJECTIVE: It is well known that laryngeal squamous cell carcinoma is strongly related to tobacco and alcohol consumption. Accumulating evidence suggests that alterations of detoxification enzymes, such as glutathione S-transferases and N-acetyltransferases, influence the risk of cancers associated with tobacco smoke and alcohol.
METHODS: This was a retrospective case-control study. The study group consisted of 88 Greek patients with laryngeal squamous cell carcinoma; there were also 102 control subjects. Frequencies of the genotypes GSTT1, GSTM1, GSTM3 and NAT2 were evaluated by polymerase chain reaction restriction fragment polymorphism.
RESULTS: The distribution of overall genotypes was 55.68 per cent rapid acetylator and 44.32 per cent slow acetylator in patients, and 36.27 per cent rapid acetylator and 63.72 per cent slow acetylator in controls. The odds ratio for rapid acetylator status in cases versus controls was 2.207 (95 per cent confidence interval 1.23-3.95, p = 0.0087).
CONCLUSION: This study demonstrated a significant relationship between rapid acetylator genotypes and laryngeal squamous cell carcinoma in a Greek population.

Blomquist T, Crawford EL, Mullins D, et al.
Pattern of antioxidant and DNA repair gene expression in normal airway epithelium associated with lung cancer diagnosis.
Cancer Res. 2009; 69(22):8629-35 [PubMed] Free Access to Full Article Related Publications
In previous studies, we reported that key antioxidant and DNA repair genes are regulated differently in normal bronchial epithelial cells of lung cancer cases compared with non-lung cancer controls. In an effort to develop a biomarker for lung cancer risk, we evaluated the transcript expressions of 14 antioxidant, DNA repair, and transcription factor genes in normal bronchial epithelial cells (HUGO names CAT, CEBPG, E2F1, ERCC4, ERCC5, GPX1, GPX3, GSTM3, GSTP1, GSTT1, GSTZ1, MGST1, SOD1, and XRCC1). A test comprising these 14 genes accurately identified the lung cancer cases in two case-control studies. The receiver operating characteristic-area under the curve was 0.82 (95% confidence intervals, 0.68-0.91) for the first case-control set (25 lung cancer cases and 24 controls), and 0.87 (95% confidence intervals, 0.73-0.96) for the second set (18 cases and 22 controls). For each gene included in the test, the key difference between cases and controls was altered distribution of transcript expression among cancer cases compared with controls, with more lung cancer cases expressing at both extremes among all genes (Kolmorogov-Smirnov test, D = 0.0795; P = 0.041). A novel statistical approach was used to identify the lower and upper boundaries of transcript expression that optimally classifies cases and controls for each gene. Based on the data presented here, there is an increased prevalence of lung cancer diagnosis among individuals that express a threshold number of key antioxidant, DNA repair, and transcription factor genes at either very high or very low levels in the normal airway epithelium.

Yu KD, Fan L, Di GH, et al.
Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1.
Breast Cancer Res Treat. 2010; 121(2):485-96 [PubMed] Related Publications
Mu class of Glutathione-S-transferase (GSTM) genes arrange in a tandem on chromosome 1p13.3. The relationship between genetic variants in the GSTM1-5 gene cluster and breast cancer is still ambiguous. In the present study, 17 tagging single-nucleotide polymorphisms (SNPs) covering the GSTMs cluster were originally selected and 11 validated SNPs were used for genotyping 921 cases and 711 controls. The association analyses were performed according to the absence or presence of GSTM1. In the GSTM1-/- group, the allele frequency of one SNP in GSTM3 was significantly different between cases and controls (P = 2.0 x 10(-4), corrected P = 0.001), with odds ratio of 1.75 (95% confidence interval, 1.26-2.44). The observed association in the GSTM1-/- group was successfully replicated in an independent population set (familial/early-onset breast cancer cases, n = 267; community-based controls, n = 667). The combined P values were robust (10(-6)) and the false positive report probability (FPRP) values were low. In contrast, no susceptibility allele/haplotype was identified when the GSTM1 gene was present. Based on epidemiological observations, we further identified two genetic variants in the GSTM3 locus accounting for differential expression of GSTM3 in normal breast tissues by such means as altering binding of RNA-pol-II. Protective genotypes were correlated with higher GSTM3 expression levels. In conclusion, SNPs/haplotypes in the GSTM3 gene within the GSTMs gene cluster are likely to contribute to breast cancer risk when the GSTM1 is absent. We infer that GSTM3 catalyzing ability in normal breast tissue might protect against breast carcinogenesis.

Zhang Y, Hughes KJ, Zahm SH, et al.
Genetic variations in xenobiotic metabolic pathway genes, personal hair dye use, and risk of non-Hodgkin lymphoma.
Am J Epidemiol. 2009; 170(10):1222-30 [PubMed] Free Access to Full Article Related Publications
From 1996 to 2000, the authors conducted a population-based case-control study among Connecticut women to test the hypothesis that genetic variation in xenobiotic metabolic pathway genes modifies the relation between hair dye use and risk of non-Hodgkin lymphoma. No effect modifications were found for women who started using hair dyes in 1980 or afterward. For women who started using hair dye before 1980 as compared with never users, a statistically significantly increased risk of non-Hodgkin lymphoma was found for carriers of CYP2C9 Ex3-52C>T TT/CT genotypes (odds ratio (OR) = 2.9, 95% confidence interval (CI): 1.4, 6.1), CYP2E1 -332T>A AT/AA genotypes (OR = 2.0, 95% CI: 1.2, 3.4), a homozygous or heterozygous 3-base-pair deletion in intron 6 of GSTM3 (OR = 2.3, 95% CI: 1.3, 4.1), GSTP1 Ex5-24A>G AA genotypes (OR = 1.8, 95% CI: 1.1, 2.9), or NAT2 genotypes conferring intermediate/rapid acetylator status (OR = 1.6, 95% CI: 1.0, 2.7). The observed associations were mainly seen for follicular lymphoma. In contrast, no significantly increased risk was observed for starting hair dye use before 1980 (relative to never use) among women who were homozygous wild-type for the CYP2C9, CYP2E1, or GSTM3 polymorphisms, women carrying 1 or 2 copies of the variant GSTP1 allele, or women who were slow NAT2 acetylators. A possible role of genetic variation in xenobiotic metabolism in the carcinogenicity of hair dye use needs to be confirmed in larger studies.

Khrunin AV, Moisseev A, Gorbunova V, Limborska S
Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients.
Pharmacogenomics J. 2010; 10(1):54-61 [PubMed] Related Publications
Platinum drugs are among the most active and widely used agents in the treatment of different cancers. However, the great individual variability in both outcome and toxicity of platinum chemotherapy requires the identification of genetic markers that can be used to screen patients before treatment. In this study, 21 polymorphisms in 10 genes, the protein activities of which may be addressed in different aspects of cisplatin metabolism, were tested for correlations with efficacy and toxicity of cisplatin-cyclophosphamide regimen in 104 ovarian cancer patients. The glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism was strongly associated with progression-free survival (chi(2)=12.12, P=0.002). The allelic status of the GSTA1 -69 C>T polymorphism correlated with the overall survival: patients with T/T genotype survived longer than C/C carriers (P=0.044). Thrombocytopenia, anemia and neuropathy were less frequent among patients with the GSTM1-null or GSTM3 intron 6 AGG/AGG genotypes. Severe neutropenia was associated with the TP53 72 Pro/Pro, XPD 312 Asp/Asn and XRCC1 399 Arg/Arg genotypes. A higher risk of nephrotoxicity was noted for patients with the heterozygous ERCC1 19007 T/C and 8092 C/A genotypes. No correlations were found between genotypes and complete tumor responses.

Mitra AP, Pagliarulo V, Yang D, et al.
Generation of a concise gene panel for outcome prediction in urinary bladder cancer.
J Clin Oncol. 2009; 27(24):3929-37 [PubMed] Free Access to Full Article Related Publications
PURPOSE: This study sought to determine if alterations in molecular pathways could supplement TNM staging to more accurately predict clinical outcome in patients with urothelial carcinoma (UC).
PATIENTS AND METHODS: Expressions of 69 genes involved in known cancer pathways were quantified on bladder specimens from 58 patients with UC (stages Ta-T4) and five normal urothelium controls. All tumor transcript values beyond two standard deviations from the normal mean expression were designated as over- or underexpressed. Univariate and multivariable analyses were conducted to obtain a predictive expression signature. A published external data set was used to confirm the potential of the prognostic gene panels.
RESULTS: In univariate analysis, six genes were significantly associated with time to recurrence, and 10 with overall survival. Recursive partitioning identified three genes as significant determinants for recurrence, and three for overall survival. Of all genes identified by either univariate or partitioning analysis, four were found to significantly predict both recurrence and survival (JUN, MAP2K6, STAT3, and ICAM1); overexpression was associated with worse outcome. Comparing the favorable (low or normal) expression of > or = three of four versus < or = two of four of these oncogenes showed 5-year recurrence probability of 41% versus 88%, respectively (P < .001), and 5-year overall survival probability of 61% versus 5%, respectively (P < .001). The prognostic potential of this four-gene panel was confirmed in a large independent external cohort (disease-specific survival, P = .039).
CONCLUSION: We have documented the generation of a concise, biologically relevant four-gene panel that significantly predicts recurrence and survival and may also identify potential therapeutic targets for UC.

Malik MA, Upadhyay R, Mittal RD, et al.
Role of xenobiotic-metabolizing enzyme gene polymorphisms and interactions with environmental factors in susceptibility to gastric cancer in Kashmir Valley.
J Gastrointest Cancer. 2009; 40(1-2):26-32 [PubMed] Related Publications
BACKGROUND: Kashmir Valley has elevated incidence rate of gastric cancer (GC) and several environmental, host genetic factors have been suspected for it. Xenobiotic carcinogen exposure and interindividual differences in its cellular metabolism may modulate susceptibility to GC.
AIM OF THE STUDY: The aim of this study is to investigate the role of genetic variants of xenobiotic-metabolizing genes with susceptibility to GC in Kashmir Valley.
METHODS: A case-control study was performed in 303 subjects (108 GC and 195 healthy controls) to analyze the association of polymorphisms in GSTM1, GSTT1, GSTP1, GSTM3, CYP1A1, and CYP2E1 genes in susceptibility to GC in Kashmir Valley. All subjects were genotyped through polymerase chain reaction-restriction fragment length polymorphism.
RESULTS: GSTM1null and CYP2E1c1c2 genotypes imparted risk for GC (odds ratio [OR] = 1.98, 95% confidence interval [95%CI] = 1.22-3.21, P = 0.006 and OR = 2.56, 95%CI = 1.25-5.25, P = 0.010, respectively). GSTM3AB genotype/B allele was found to be associated with low risk for GC. Smokers and high salted tea consumers themselves were at higher risk for GC (OR = 8.98, 95%CI = 5.16-15.62, P = 0.0001 and OR = 14.78, 95%CI = 8.02-27.23, P = 0.0001, respectively). Cancer risk was further enhanced in smokers with the GSTM1null genotype.
CONCLUSION: The results suggest that GSTM1null, GSTM3AB, and CYP2E1c1c2 genotypes modulate the risk of GC whereas GSTM1null genotypes enhance the risk of GC for smokers in the Kashmir population.

Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women.
Breast Cancer Res Treat. 2010; 119(2):463-74 [PubMed] Related Publications
Recent findings indicate a greater risk of postmenopausal breast cancer with estrogen-progestagen therapy than estrogen monotherapy, and more so for current than past use. Few studies have examined individual genetic susceptibility to the effects of menopausal hormone therapy. We used two population-based case-control studies with 3,155 postmenopausal breast cancer patients and 5,496 controls to evaluate modification of breast cancer risk associated with duration of hormone use by genes involved in hormone metabolism and detoxification. Twenty-eight polymorphisms in eight genes of phase I (CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP3A5, CYP3A7) and nine genes of phase II enzymes (COMT, GSTM1, GSTM3, GSTP1, GSTT1, SULT1A1, UGT1A1, UGT1A6, UGT2B7) were genotyped. The risk associated with duration of use of combined estrogen-progestagen therapy was significantly modified by genetic polymorphisms located in CYP1B1, GSTP1, and GSTT1. In homozygote carriers of the CYP1B1_142_G and the CYP1B1_355 _T variant alleles, adjusted odds ratios (OR) per year of use were 1.06 (95% confidence interval (CI) = 1.02-1.09) and 1.06 (95% CI = 1.03-1.09), respectively, compared with 1.02 (95% CI = 1.01-1.03) in non-carriers of either polymorphism (p(interaction) = 0.01). Carriers of the functional GSTT1 allele and the GSTP1_341_T allele were at significantly higher risks associated with hormone use compared with non-carriers (p(interaction) = 0.0001 and 0.02). CYP1A1_2452_C>A significantly reduced the risk associated with duration of use of estrogen monotherapy (p(interaction) = 0.01). The finding regarding GSTT1 was still statistically significant after corrections for multiple comparisons. Postmenopausal breast cancer risk associated with hormone therapy may be modified by genetically determined variations in phase I and II enzymes involved in steroid hormone metabolism.

Koutros S, Berndt SI, Sinha R, et al.
Xenobiotic metabolizing gene variants, dietary heterocyclic amine intake, and risk of prostate cancer.
Cancer Res. 2009; 69(5):1877-84 [PubMed] Free Access to Full Article Related Publications
We recently reported that heterocyclic amines (HCA) are associated with prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We now use extensive genetic data from this resource to determine if risks associated with dietary HCAs {2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP); 2-amino-3,8-dimethylimidazo[4,5-b]quinoxaline (MeIQx); and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx)} from cooked meat are modified by single nucleotide polymorphisms (SNP) in genes involved in HCA metabolism (CYP1A1, CYP1A2, CYP1B1, GSTA1, GSTM1, GSTM3, GSTP1, NAT1, NAT2, SULT1A1, SULT1A2, and UGT1A locus). We conducted a nested case-control study that included 1,126 prostate cancer cases and 1,127 controls selected for a genome-wide association study for prostate cancer. Unconditional logistic regression was used to estimate odds ratios (OR), 95% confidence intervals (95% CI), and P values for the interaction between SNPs, HCA intake, and risk of prostate cancer. The strongest evidence for an interaction was noted between DiMeIQx and MeIQx and the polymorphism rs11102001 downstream of the GSTM3 locus (P(interaction) = 0.001 for both HCAs; statistically significant after correction for multiple testing). Among men carrying the A variant, the risk of prostate cancer associated with high DiMeIQx intake was 2-fold greater than that with low intake (OR, 2.3; 95% CI, 1.2-4.7). The SNP rs11102001, which encodes a nonsynonymous amino acid change P356S in EPS8L3, is a potential candidate modifier of the effect of HCAs on prostate cancer risk. The observed effect provides evidence to support the hypothesis that HCAs may act as promoters of malignant transformation by altering mitogenic signaling.

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