2944

GSTM1

glutathione S-transferase mu 1;GSTM1;glutathione S-transferase mu 1

GST HB subunit 4|GST class-mu 1|HB subunit 4|S-(hydroxyalkyl)glutathione lyase|glutathione S-alkyltransferase|glutathione S-aralkyltransferase|glutathione S-aryltransferase|glutathione S-transferase M1|glutathione S-transferase Mu 1

1p13.3

protein-coding

BACKGROUND: Oxaliplatin is used as a neo-adjuvant therapy in hepatic colorectal carcinoma metastasis. This treatment has significant side effects, as oxaliplatin is toxic to the sinusoidal endothelial cells and can induce sinusoidal obstruction syndrome (SOS), which is related to decreased overall survival. Glutathione has an important role in the defence system, catalysed by glutathione S-transferase (GST), including two non-enzyme producing polymorphisms (GSTM1-null and GSTT1-null). We hypothesise that patients with a non-enzyme producing polymorphism have a higher risk of developing toxic injury owing to oxaliplatin. METHODS: In the nontumour-bearing liver, the presence of SOS was studied histopathologically. The genotype was determined by a semi-nested PCR. RESULTS: Thirty-two of the 55 (58%) patients showed SOS lesions, consisting of 27% mild, 22% moderate and 9% severe lesions. The GSTM1-null genotype was present in 25 of the 55 (46%). Multivariate analysis showed that the GSTM1-null genotype significantly correlated with the presence of (moderate-severe) SOS (P=0.026). CONCLUSION: The GSTM1-null genotype is an independent risk factor for SOS. This finding allows us, in association with other risk factors, to conceive a potential risk profile predicting whether the patient is at risk of developing SOS, before starting oxaliplatin, and subsequently might result in adjustment of treatment.

Polymorphism of GSTT1 and GSTM1 variant genes of phase II biotransformation of xenobiotics was studied in 181 patients with lung cancer. Null genotype frequency in cancer patients was higher than in healthy subjects. It was still higher in metastatic cancer disseminated to the regional lymph nodes as compared with localized tumor.

BACKGROUND: Environment-gene interaction in oral carcinogenesis is well demonstrated by phase I and II enzymes that are involved in the metabolism of carcinogens. This study investigated the association of glutathione S-transferase (GST)T1 and GSTM1 genotypes of phase II enzyme genes with risk for, age of onset, and neck lymph node metastasis (LNM) in areca-associated oral squamous cell carcinoma (OSCC). METHODS: A total of 114 OSCC male patients and 100 male controls were recruited. All subjects were areca users and tobacco smokers. DNA was obtained from peripheral blood samples. Genotyping of GSTT1 (non-null/null) and GSTM1 (non-null/null) was determined by polymerase chain reaction (PCR) analysis using specific primers that only amplify non-null alleles. RESULTS: No association was found between GST genotype and the risk of OSCC based on case-controls. Patients with the GSTT1 null genotype were older at onset (P = 0.03). Those with the GSTM1 null genotype had a higher incidence of neck LNM than those with the GSTM1 non-null genotype (P = 0.01). Patients with the GSTM1/GSTT1 null genotype appeared to have later onset and a higher incidence of neck LNM than those carrying the opposite genotype. CONCLUSION: The GST genotypes may be important markers for the age of onset and risk of metastasis in OSCC. The data also suggest that the various GST isoforms may be differentially involved in development or progression of OSCC.

Glutathione S-transferases (GST) are antioxidant enzymes and oxidative stress markers in oral carcinogenesis. They present a system of polymorphic proteins. Some variants are associated with increased sensitivity to toxic compounds, as it is known for the GSTM1-null variant allele. However, the influence of the GSTM1 allele variant genotype on GSTM1-mRNA quantity in oral squamous cell carcinoma (OSCC) and normal mucosa as well as the impact on prognosis remains unclear. The genotype for GSTM1 (mutation vs. wild type) was determined by polymerase chain reaction (PCR) using genomic DNA extracted from peripheral blood from 28 OSCC patients. From the same patients, 28 pairs of OSCC cells and normal oral mucosal cells were obtained by brush biopsy. mRNA was extracted from these paired samples and the expression levels of GSTM1 were examined by real-time reverse transcriptase qPCR (RT-qPCR). The mRNA expression of the OSCC samples was normalized against an external standard, as well as to the corresponding normal mucosa. The coincidence of GSTM1 genotype and GSTM1-mRNA-expression level was examined. In 15 patients (54%), the null genotype GSTM1 was present. In the GSTM1-null allele group, the GSTM1 gene expression level was determined at 1.63 (mean: 3.08; SD 3.4) folds vs. 3.6 (mean: 10.5; SD 14.2) folds in the group with the positive genotype (p=0.06), if calibrated vs. individual normal mucosa. More T3 and T4 OSCCs (+38%), higher UICC stadia (+38%) and more lymphatic metastasis (+28%) were seen in the group with the negative allele. Furthermore, positive GSTM1 genotype and enhanced GSTM1 gene expression was accompanied with increased tumor size, lymphatic metastasis status and UICC stadium. A coincidence of null type GSTM1 and lowered GSTM1 gene expression was observed. The larger tumors and more frequent lymph node metastases in this group could be explained by the insufficient cell protection by GST.

PURPOSE: We outlined the putative significance of GST in renal cell carcinoma biology by investigating the influence of its deletion polymorphisms on renal cell carcinoma progression. MATERIALS AND METHODS: Genomic DNA was purified from peripheral blood leukocytes. GSTM1 and GSTT1 genes were polymerase chain reaction amplified and gene fragments were separated by agarose gel electrophoresis. Intact GSTM1 and GSTT1 alleles were identified by the presence of 230 and 480 bp fragments, respectively. Genotypes were associated with clinicopathological variables and survival. RESULTS: Of 147 patients with renal cell carcinoma 80 (54%) had the GSTM1 null and 27 (18%) had the GSTT1 null genotype. The GST genotype distribution did not differ significantly from that in 112 controls without renal cell carcinoma. However, the GSTM1 null genotype was associated with 60% lower odds of the papillary subtype (OR 0.40, 95%

BACKGROUND: To assess the impact of polymorphisms in Glutathione S-transferase (GST) -P1, -M1, and -T1 on self-reported chemotherapy-induced long-term toxicities in testicular cancer survivors (TCSs). METHODS: A total of 238 TCSs, who had received cisplatin-based chemotherapy at median twelve years earlier, had participated in a long-term follow-up survey which assessed the prevalence of self-reported paresthesias in fingers/toes, Raynaud-like phenomena in fingers/toes, tinnitus, and hearing impairment. From all TCSs lymphocyte-derived DNA was analyzed for the functional A-->G polymorphism at bp 304 in GSTP1, and deletions in GST-M1 and GST-T1. Evaluation of associations between GST polymorphisms and self-reported toxicities included adjustment for prior treatment. RESULTS: All six evaluated toxicities were significantly associated with the cumulative dose of cisplatin and/or bleomycin. Compared to TCSs with either GSTP1-AG or GSTP1-AA, the 37 TCSs with the genotype GSTP1-GG, were significantly less bothered by paresthesias in fingers and toes (p = 0.039, OR 0.46 [0.22-0.96] and p = 0.023, OR 0.42 [0.20-0.88], respectively), and tinnitus (p = 0.008, OR 0.33 [0.14-0.74]). Furthermore, absence of functional GSTM1 protected against hearing impairment (p = 0.025, OR 1.81 [1.08-3.03]). CONCLUSION: In TCSs long-term self-reported chemotherapy-induced toxicities are associated with functional polymorphisms in GSTP1 and GSTM1. Hypothetically, absence of GST-M1 leaves more glutathione as substrate for the co-expressed GST-P1. Also intracellular inactivation of pro-apoptotic mediators represents a possible explanation of our findings. Genotyping of these GSTs might be a welcomed step towards a more individualized treatment of patients with metastatic testicular cancer.