A study of the association of glutathione S-transferase M1/T1 polymorphisms with susceptibility to vitiligo in Egyptian patients

Abstract: Background: The association of glutathione S-transferases M1/T1 (GSTM1/T1) null polymorphisms with vitiligo was proposed in several studies including two Egyptian studies with contradictory results. Objective: The aim here was to assess the association between GSTM1/T1 null polymorphisms and the susceptibility to vitiligo in a larger sample of Egyptian patients with generalized vitiligo. Methods: This study included 122 vitiligo patients and 200 healthy controls that were age, and gender matched. Assessment of GSTM1/T1 gene polymorphisms was done using a multiplex polymerase chain reaction (PCR). Results: Increased odds of generalized vitiligo was observed with the null genotypes of GSTM1 and GSTT1 polymorphisms (P<0.05). Controls with GSTM1 null/GSTT1+ heterozygosis presented with a 2.97 odds protection from having generalized vitiligo (OR=2.97, 95%CI=1.1-7.7) (P=0.02) compared with patients. Study Limitations: Small sample size of patients. Conclusions: This study showed a significant trend towards an association with the combination of the GSTM1/GSTT1 double null polymorphism and generalized vitiligo. Individuals with GSTM1 null/GSTT1+ heterozygosis have a 2.97 odds protection from having generalized vitiligo compared with patients. It was is the first time, to our knowledge, that such an association has been reported.

The changes in expression of high-sensitivity C-reactive protein, glutathione S-transferase Pi and annexin A5 in elderly patients with old myocardial infarction and the clinical significance / 中华老年医学杂志

Objective To study the changes in expression of high-sensitivity C-reactive protein (hsCRP),glutathione S-transferase Pi(GSTPi)and annexin A5 (AnxA5)in elderly patients with old myocardial infarction and the clinical significance.Methods Serum levels of GSTPi and AnxA5 were measured by ELISA and the level of hs-CRP was measured by immunoturbidimetry in elderly patients with old myocardial infarction (n =185)from December 2012 to November 2015.Results Along with the increasing coronary artery stenosis,GSTPi level was decreased and AnxA5/hs-CRP levels were increased in elderly patients with old myocardial infarction.In comparison between coronary artery stenosis ＞ 95％ group versus stenosis of 55％-65％ group,GSTPi was(190.0±37.0)μg/L vs.(289.0 ±86.0)μg/L,AnxA5 was(33.9±4.0)μg/L vs.(8.1 ± 2.9) μg/L,and hs-CRP was (15.3 ± 1.3) mg/L vs.(5.9 ± 0.8) mg/L with statistically significant differences(all P＜0.01).There were significant differences between LVEF 30％ group[GSTPi(198.0±39.0) μg/L,AnxA5(38.9±5.1)μg/L and hs-CRP(17.9± 1.9)mg/L]and LVEF 40％-54％ group[GSTPi(219.0± 61.0)μg/L,AnxA5 (12.9±3.9)μg/L and hs-CRP(10.1 ± 1.0) mg/L] (all P＜0.01).There were significant differences between NYHA Ⅳ group [GSTPi (171.0 ± 43.0) μg/L,AnxA5 (18.1 ± 5.0) μg/L and hs-CRP (16.9±2.1)mg/L]and NYHAⅠgroup[GSTPi(295.0±91.0)μg/L,AnxA5(7.3±3.1)μg/L and hs-CRP (7.8± 1.3)mg/L](all P＜0.01).Conclusions The expression of GSTPi,AnxA5 and hs-CRP in elderly patients with old myocardial infarction may become the new indicators to forecast the degrees of coronary artery stenosis and heart failure.

Association between glutathione S-transferase pi gene polymorphism and adverse reaction of high-dose methotrexate in children with acute lymphoblastic leukemia / 中国肿瘤临床

Objective:To investigate the association between glutathione S-transferase pi (GSTP1) gene polymorphism and toxici-ties related to high-dose methotrexate (HD-MTX) in children with acute lymphoblastic leukemia (ALL). Methods:GSTP1 genotypes and allelic frequencies in 51 children with ALL were determined by Nest PCR, denaturing gel gradient electrophoresis (DGGE), and DNA sequencing. HD-MTX adverse reactions were analyzed using the National Cancer Institute Common Toxicity Criteria (NCICTC). Results:We identified three SNPs of GSTP1, including rs1695 (A313G), rs1138272 (G439T), and rs4891 (T555C). The wild types, het-erozygous types, and homozygous types of GSTP1 rs1695/rs4891 polymorphisms were detected in 32 cases (62.7%), 16 cases (31.4%), and 3 cases (5.9%), respectively. GSTP1 rs1695/rs4891 polymorphisms included only one heterozygous type and one homozygous type. The allele frequencies of the three SNPs were 21.6%, 2.9%, and 21.6%. The AG+GG/TC+CC genotype of GSTP1 rs1695/rs4891 was associated with decrease in the odds of peripheral hemoglobin (OR=0.25, 95%CI=0.06-1.00, P=0.049). The AG+GG/TC+CC genotype of GSTP1 rs1695/rs4891 in standard and intermediate-risk ALL children was significantly correlated with higher odds of gastrointesti-nal toxicity (OR=0.125, 95%CI=0.02-0.78, P=0.026). Conclusion:GSTP1 rs1695 (A313G)/rs4891 (T555C) gene polymorphism is as-sociated with the reduction of peripheral hemoglobin in ALL children and with the odds of gastrointestinal toxicity in standard and inter-mediate-risk ALL children who receive high-dose methotrexate.

Association between Ile105Val polymorphism of GSTP1 and sensitivity to platinum-based chemotherapy in advanced gastric cancer: a Meta-analysis / 国际肿瘤学杂志

Objective To quantitatively evaluate the association between Ile105Val polymorphism of glutathione S-transferase pi (GSTP1) and sensitivity to platinum-based chemotherapy in advanced gastric cancer.Methods The relevant published literatures about Ile105Val polymorphism of GSTP1 and sensitivity to platinum-based chemotherapy in gastric cancer were retrieved from China National Knowledge Internet (CNKI),VIP,Chinese Biomedical Literature Data (CBM),Wan-Fang databases,PubMed,EMBASE and Cochrane Library.Clinical response (complete response and partial response) was employed to estimate chemosensitivity.Meta-analysis was conducted by the RevMan 5.2 software,odds ratio (OR) with 95％ confidence interval (CI) were calculated.Publication bias was identified using Stata 12.0 software.Results A total of 724 cases from 6 case-control trials were included.The results of Meta-analysis showed the different statistical significance was found between GSTP1 Ilel05Val polymorphism and clinical response in the follow genotypes [GG+GA vs AA:OR =2.38,95％CI (1.29 ～4.38); GG vs GA + AA:OR =3.66,95％CI (1.18 ～11.39) ; GG vs AA:OR =4.42,95％ CI (1.28 ～ 15.26)] and Asian population subgroups [GG + GAvs AA:OR =2.93,95％ CI (1.33 ～ 6.48)].Conclusion Polymorphism of GSTP1 Ile105Val(A/G) may be associated with platinum-based chemosensitivity in advanced gastric cancer.

Genetic Polymorphism of GSTP1: Prediction of Clinical Outcome to Oxaliplatin/5-FU-based Chemotherapy in Advanced Gastric Cancer

The aim of this study was to evaluate the predictive value of the polymorphism Glutathione S-transferase P1 (GSTP1) Ile(105)Val on oxaliplatin/5-FU-based chemotherapy in advanced gastric cancer. Patients with advanced gastric cancer accepted oxaliplatin/5-FU-based chemotherapy as first-line chemotherapy were investigated. GSTP1 Ile(105)Val polymorphism was detected by TaqMan-MGB probe allelic discrimination method. Response to treatment was assessed by disease controlled rate. Time to progression, overall survival and toxicities were recorded. Final patient outcomes were as follows: the allele frequencies of GSTP1 were (105)Ile/(105)Ile 52%, (105)Ile/(105)Val 41% and (105)Val/(105)Val 7%. For patients with (105)Ile/(105)Ile and those with at least one (105)Val allele, disease control rate was 39% and 71% (P=0.026), respectively; median time to progression was 4.0 and 7.0 months (P=0.002); median overall survival time was 7.0 and 9.5 months (P=0.002). Neurological toxicity was more frequently occurred in patients with two (105)Ile alleles (P=0.005). In conclusion, patients with at least one (105)Val allele have better prognosis and response to oxaliplatin/5-FU-based regimen as first-line treatment for patients with advanced gastric cancer.

An Analysis of HER-2/neu, ERCC1, and GST-pi in Advanced Non-Small Cell Lung Cancer Patients Who are Treated with Platinum-based Chemotherapy

BACKGROUND: Platinum-based chemotherapy has shown to be an effective first-line treatment for patients with advanced stage, unresectable non-small cell lung cancer (NSCLC). We evaluated the response rate to combination chemotherapy with cisplatin and taxane, and the significance of the HER-2/neu, ERCC1, and GST-pi status as predictive markers for the tumor response. METHODS: The HER-2/neu, ERCC1, and GST-pi status were analyzed in the biopsy specimens obtained from 35 patients with advanced stage NSCLC prior to cisplatin plus either paclitaxel or docetaxel chemotherapy. RESULTS: The response rate of the tumors to combination chemotherapy was 62.9% (22/35). HER-2/neu was amplified in 51.4% (18/35) of the tumors, and this was observed exclusively in patients with progressive disease (p=0.014). ERCC1 was overexpressed in 77.2% of the specimens (27/35), and this showed a tendency to correlate with the tumor response (p=0.057). GST-pi was detected in 85.7% of the specimens (30/35). Seventy-seven percent of the patients with a negative HER-2/neu and positive ERCC1 status showed a partial response, which was in contrast to only a 25% response rate for the patients with a positive HER-2/neu and negative ERCC1 status (p=0.006). The overall survival was prolonged in the patients without HER-2/neu amplification (15 vs 8.5 months, respectively, p=0.008). On multivariate analysis, the HER-2/neu status remained the significant predictor of survival (p=0.005). CONCLUSIONS: A combination of the ERCC1, HER-2/neu status may define a subset of patients with the most favorable response to combination chemotherapy regimens for treating advanced NSCLC.

Comparative analysis of the prevalence of the glutathione S-transferase (GST) system in malignant and benign thyroid tumor cells

CONTEXT AND OBJECTIVE: When null, the mu and theta genes of the glutathione S-transferase system (GSTM1 and GSTT1, respectively) are related to malignant tumors affecting the lungs, colon, prostate, bladder and head and neck. In the thyroid, the appearance of cancer has been correlated with deletion of these genes. The aim of this study was to compare the frequencies of these genes in patients with benign and malignant tumors of the thyroid gland. DESIGN AND SETTINGS: This was a cross-sectional clinical trial carried out in the Head and Neck Surgery Division, Faculdade de Medicina da Santa Casa de São Paulo. METHODS: Samples of thyroid tissue were collected from 32 patients and divided into two groups: benign tumor (A) and malignant tumor (B). After DNA extraction, the genes were amplified using PCR. RESULTS: The B group presented four cases of positive genotyping for both genes, seven positive for GSTT1 and negative for GSTM1, two negative for GSTT1 and positive for GSTM1, and only one case of double negative. The A group showed 11 cases with positive genotyping for both genes and none with the double negative genotype. CONCLUSION: In this study, there was no relationship between the presence of the GSTT1 and GSTM1 genes and the benign and malignant thyroid tumors.

CONTEXTO E OBJETIVO: Os genes do sistema glutationa S-transferase mu e theta (GSTM1 e GSTT1, respectivamente), quando nulos, apresentam relação com tumores malignos de pulmão, cólon, próstata, bexiga e cabeça e pescoço, podendo nesses casos ser utilizados como marcadores tumorais. Na tireóide, o surgimento do câncer tem sido relacionado à deleção desses genes. Assim, o objetivo deste estudo foi comparar a freqüência dos genes GSTM1 e GSTT1 em pacientes com tumores benignos e malignos da glândula tireóide. TIPO DE ESTUDO E LOCAL: Estudo clínico transversal, realizado na Faculdade de Ciências Médicas da Santa Casa de São Paulo. MÉTODOS: Amostras de tecido tireoidiano foram coletados de 32 pacientes e divididas em dois: tumor benigno (A) e carcinoma (B). Após extração do DNA os genes foram amplificados em reação de polimerase em cadeia. RESULTADOS: O grupo B apresentou 4 casos de genótipo positivo para ambos os genes, 7 positivos para GSTT1 e negativos para GSTM1, 2 negativos para GSTT1 e positivos para GSTM1, e apenas 1 caso duplo negativo. Já o grupo A mostrou 11 casos com genótipo positivo para ambos os genes e nenhum com o genótipo duplo negativo. CONCLUSÃO: Não há relação entre a presença dos genes GSTT1 e GSTM1 com o carcinoma bem diferenciado e os tumores benignos da tireóide em nossos casos.

Association of the GSTP1 and NQO1 Polymorphisms and Head and Neck Squamous Cell Carcinoma Risk

The GSTP1 and NQO1 have been reported to be associated with an increased risk for smoking related head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to determine the effect of these metabolic gene polymorphisms on the risk of HNSCC. The study population included 294 histologically confirmed HNSCC cases and 333 controls without cancer. Genotyping analysis of the GSTP1 Ile105Val and NQO1 Trp139Arg genes was performed by polymerase chain reaction-based techniques on DNA prepared from peripheral blood. The Mantel-Haenszel chi-square test was used for statistical analysis. The allele frequencies of the GSTP1 and NQO1 polymorphisms were not statistically significant between cases and controls. In analyzing the association between smoking amounts and genetic polymorphisms, GSTP1 and NQO1 polymorphisms were associated with cigarette smoking amounts in cases. G allele containing genotypes in GSTP1 and T allele containing genotypes in NQO1 were associated with a tobacco dose-dependent increase in risk of HNSCC and these genotype distributions were statistically significant (p<0.05). We found that the GSTP1 105Val allele and NQO1 139Arg allele were associated with tobacco dose-dependent increase in risk of HNSCC. GSTP1 and NQO1 genotype polymorphisms may play an important role in the development of smoking related HNSCC.

GSTM1 and GSTP1 Polymorphisms as Potential Factors for Modifying the Effect of Smoking on Inflammatory Response

Inflammation has been known to be an important underlying condition for development of various diseases including cancer. The aims of this study were to investigate whether tobacco smoke exposure increases the level of inflammation biomarkers and the GSTM1 and GSTP1 gene polymorphisms are associated with inflam matory response due to tobacco smoke exposure. We measured urinary cotinine level in 300 healthy university students. Total serum TNF-alpha levels and blood WBC counts were determined to evaluate inflammatory response. Allelic loss of the GSTM1 and the GSTP1 (Ile105Val) polymorphism were determined by PCR and RFLP. Tobacco smoke exposure was found to be associated with increase of both TNF-alpha level and WBC count. Particularly, smokers with combination of GSTM1 null and GSTP1 AG or GG genotypes showed higher TNF-alpha level than those with the other genotype combinations (p=0.07). This result suggests that smoking may induce inflammation measured as TNF-alpha level or WBC count and combinations of the GSTM1 and GSTP1 polymorphisms may modify the effect of smoking on serum TNF-alpha level.

GSTM1 and GSTP1 Polymorphisms as Potential Factors for Modifying the Effect of Smoking on Inflammatory Response

Inflammation has been known to be an important underlying condition for development of various diseases including cancer. The aims of this study were to investigate whether tobacco smoke exposure increases the level of inflammation biomarkers and the GSTM1 and GSTP1 gene polymorphisms are associated with inflam matory response due to tobacco smoke exposure. We measured urinary cotinine level in 300 healthy university students. Total serum TNF-alpha levels and blood WBC counts were determined to evaluate inflammatory response. Allelic loss of the GSTM1 and the GSTP1 (Ile105Val) polymorphism were determined by PCR and RFLP. Tobacco smoke exposure was found to be associated with increase of both TNF-alpha level and WBC count. Particularly, smokers with combination of GSTM1 null and GSTP1 AG or GG genotypes showed higher TNF-alpha level than those with the other genotype combinations (p=0.07). This result suggests that smoking may induce inflammation measured as TNF-alpha level or WBC count and combinations of the GSTM1 and GSTP1 polymorphisms may modify the effect of smoking on serum TNF-alpha level.

GSTM1, GSTT1 and GSTP1 Polymorphisms in the Korean Population

The isoenzymes of the glutathione s transferase (GST) family play a vital role in phase II of biotransformation of many substances. Using a multiplex polymerase chain reaction and a direct sequencing analysis, the frequencies of GSTM1, GSTT1, and GSTP1 polymorphisms were evaluated in 1,051 Korean male subjects. We found that 53.8% of the individuals had the GSTM1 null genotype and 54.3% had the GSTT 1 null genotype. The genotypic distribution of GSTP1 was Ile105/Ile105 in 68.4%, Ile105/ Val105 in 29.1% and Val105/Val105 in 2.5%. The most frequently observed combination of GSTM1, GSTP1 and GSTT1 genotypes was Null type/Ile105/Ile105/Null type, while the combination of Non-null type/Val105/Val105/Non-Null type was not observed. We found that the genotype distributions of three GST isoenzymes in the Koreans are similar to those reported in Asians and previously reported Koreans. We believe our results, which are represented by a large population, are reliable estimates of the frequencies of the polymorphic GST alleles in the Koreans and will help future researches on GST polymorphisms.

DNA Hypermethylation of Tumor-Related Genes in Gastric Carcinoma

The hypermethylation of the CpG islands is a common mechanism for the inactivation of tumor-related genes. In the present study, we analyzed the methylation status of genes for cell repair such as hMLH1, MGMT, and GSTP1, and a gastric cancer-specifically methylated DNA fragment, MINT 25 in gastric cancer cases and control groups. The study population consisted of 100 gastric cancer patients (50 distal and 50 proximal carcinomas), and 238 healthy controls. All genes showed more frequent hypermethylation in the cases than in the control group (p<0.0001). We investigated the association between promoter hypermethylation and relevant parameters including age, gender, alcohol consumption, smoking, and family history. There was a common hypermethylation of hMLH1 (p=0.008), MGMT (p= 0.0001), and GSTP1 (p=0.0003) in females. This study also demonstrates that hypermethylation was strongly associated with non-drinkers (MGMT, p=0.046 and MINT 25, p=0.049) and non-smokers (hMLH1, p=0.044; MGMT, p=0.0003; MINT 25, p=0.029). Moreover, the frequency of MINT 25 hypermethylation increased with age (p=0.037), and MGMT methylation was frequently detected in distal gastric cancer than in proximal type (p=0.038). Our study suggested that promoter hypermethylation of the genes involved in cell repair system and MINT 25 is associated strongly with some subgroups of primary gastric carcinoma.

Clinical Significance of p53, P-glycoprotein, and Glutathione S transferase-pi in Advanced Non-Small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: A retrospective study was performed o define the clninical significance of p53, P-glycoprotein (Pgp), and Glutathione S transferase-pi (GST-pi) immunohistochemical (IHC) expression in advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We reviewed fifty seven patients with advanced NSCLC who had undergone surgical resection or bronchoscopic biopsy between March 1997 and March 1999. IHC staining for p53, GST-pi, and Pgp was performed using formalin-fixed, paraffin-embedded specimens of the fifty seven patients. RESULTS: The IHC expression rate was 63% for p53, 28% for Pgp, and 53% for GST-pi, respectively. The median survival of the fifty seven patients was 45 weeks and the response rate was 38.6% (partial response, 22/57). The chemotherapy response and median survival of the p53 negative group (57% and 61 weeks) were better than those demonstrated by the p53 positive group (28% and 21 weeks) (p<0.05). Additionally, the GST-pi negative group showed a greater improvement of survival and response rate than the positive group (p<0.05). Pgp expression status appeared to have no significant differential effect on chemotherapy response and survival. CONCLUSION: These results suggest that immunohisto chemical staining of p53 and GST-pi may be useful in predicting the response to chemotherapy as well as survival in advanced NSCLC. However, this study is limited by its retrospective nature and the small numbers of tumors studied from a heterogenous group of patients.

Immunohistochemical Study on the Expression of Topoisomerase II alpha and Glutathione S-Transferase pi in Acute Myeloid Leukemia / 대한임상병리학회지

BACKGROUND: Topoisomerase II (topo II) is a major target of anthracyclines and epipodophyllotoxins for anticancer treatment. The expression of topo II is low in drug resistant cell lines. High levels of glutathione S-transferase (GST)pi have been associated with emergence of cell lines resistant to alkylating agents or adriamycin. METHODS: By immunostaining with paraffin embedded bone marrow tissues, the expression of topo II alpha and GSTpi was investigated in 51 patients with acute myeloid leukemia (AML), and the relation of topo II alpha and GSTpi expression to treatment response in 29 patients with AML following induction chemotherapy was also evaluated. RESULTS: Topo II positive cells varied from less than 1% to 60% of leukemic cells and 20 (39.2%) were negative for topo II (positive cells<10%). Treatment response following chemotherapy was not related to topo II. 26 (51.0%) were positive for GSTpi. GSTpi expression was related to treatment resistance of the patients following chemotherapy. In the patients who showed both topo II alpha negative and GSTpi positive, the frequency of treatment resistance following chemotherapy was high. CONCLUSIONS: This study suggests that immunostaining of topo II alpha and GSTpi with the bone marrow paraffin sections of AML patients can be useful to predict the treatment response following chemotherapy and that further study including more patients with prospective study may substantiate topo II alpha and GSTpi as multidrug resistant markers.

Immunohistochemical Study of Pi Class of Glutathione S-Transferase in Psoriasis and Eczematous Dermatitis

BACKGROUND: Glutathione S-transferase(GST) is a family of isoenzymes that play an important role in protecting cells from cytotoxic and carcinogenic agents. Strong activities of GST-Pi in the epithelial tissues was observed in the upper layer of skin, gastrointestinal tract and placenta which have been exposed to exogenous chemicals. OBJECTIVE: This study was done to observe the distribution pattern of GST-Pi in normal, acute and chronic psoriasis or eczematous dermatitis, using paraffin-embedded human skin tissues. METHODS: Twenty-one psoriatic and twenty-six eczematous dermatitis specimens were observed by immunohistochemical staining using an anti-rabbit GST-Pi polyclonal antibody. RESULTS: Stainining reaction for the GST is weakly to moderately stained in the normal epidermis. In the acute stage, upper layer shows weak and moderate staining in the lower epidermis of the psoriasis and eczematous dermatitis but in the chronic stage GST-Pi are noted strongly expression in upper epidermis. CONCLUSION: Immunohistochemical staining for the GST-Pi reveals a more abundant distribution in the chronic stage rather than in the acute stage of psoriasis and eczema tous dermatitis, showing no disease specificity. Therefore it is suggested that the detoxifying capacity decreases in the acute stage of above dermatosis.