Hatice Pinarbasi

Strong association between the GSTM1-null genotype and lung cancer in a Turkish population

Glutathione S-transferases are possibly related to the detoxification of many xenobiotics involved in the etiology of cancer. To investigate the role of the glutathione S-transferase M1 deletion (GSTM1-null) in lung cancer, the polymerase chain reaction was used to determine the GSTM1 genotypes of lung cancer patients (n=101) and hospital (n=206) in a Turkish population. The prevalence of the GSTM1-null genotype in the case group was 48%, compared to 18% in the control group, giving an odds ratio (OR) of 4.14 (95% confidence interval [CI]=2.36-7.27). The analysis of patients by histologic type of lung cancer (10% adenocarcinoma, 43% squamous cell carcinoma, 26% small cell carcinoma, and 11% large cell carcinoma) showed no association between histopathologic type of lung cancer and GSTM1-null genotype. When the interaction between the GSTM1-null genotype and smoking status was analyzed, among the 67 smokers, the GSTM1-null genotype was found in 37 (55%) with an OR of 2.58 (95% CI=1.00-6.73) indicating a significant association. However, no association was found between smoking exposure (<30 and > or =30 packs/year) and GSTM1-null genotype. We conclude that, in this study the null GSTM1 genotype is an independent risk factor for the development of lung cancer for Turkish population.

Polymorphisms of CYP1A1, GSTM1, GSTT1, and Prostate Cancer Risk in Turkish Population

Prostate cancer is the most common cancer among men in many countries. Although the etiology of prostate cancer largely is unknown, both genetic and environmental factors may be involved. Advanced age, androgen metabolism, and heredity-race have been reported to be possible risk factors. On the other hand, several studies indicate that genetic polymorphisms in biotransformation enzymes play a role in prostate cancer development. In this study, association of the prostate cancer risk with genotype frequencies of the Phase I (CYP1A1) and Phase II (GSTM1 and GSTT1) biotransformation enzymes was investigated in 321 Turkish individuals (152 prostate cancer patients and 169 age-matched male controls). The presence or absences of the GSTM1 and GSTT1 genes were determined by a PCR-based method. Genotypes of CYP1A1 were determined by MspI-RFLP. The prevalence of GSTM1 null genotype in the cases was 64 percent, compared to 31 percent in the control group, indicating a strong association (OR = 4.08, 95%CI = 2.50–6.69). No association was observed between either GSTT1 null genotype or CYP1A1 polymorphism and prostate cancer incidence. No statistically significant association was observed between smoking status of the patients and any of the polymorphisms studied. In conclusion, results of this study indicate that only the GSTM1 null genotype may play an important role as a risk factor for prostate cancer development in Turkish population.

The Association Between Polymorphisms in Glutathione S-Transferase (GSTM1 and GSTT1) and Lung Cancer Outcome

Background: Polymorphisms in the glutathione S-transferase (GST) family may be associated with increased risk of lung cancer, somatic changes in lung tumour tissue, and survival. We evaluated survival according to GST polymorphism in lung cancer patients. Methods: We studied DNA polymorphisms of 81 primary lung cancer patients at 2 glutathione-related loci: GSTM1, and GSTT1 that encode glutathione S-transferase-μ, and glutathione S-transferase-□. The presences of the GSTM1 and GSTT1 genes were assayed by PCR. Kaplan-Meier with log rank tests, and Cox regression models were applied in the analysis. Results: The median age of 75 males and 6 females was 60 years. Median survival of the whole population was 8 months. In the first presentation, none of the patients with GSTT1 null genotype but 30 percent of the patients with GSTT1-positive genotype had liver metastasis (p < 0.01) but GSTT1 genotype was not associated with survival. Sputum (p < 0.01) was more common in patients with GSTM1 null genotype. Subjects with the GSTM1-null genotype had shorter survival. Using a Cox proportional hazard model, GSTM1, tumor (T) factor and thoracic irradiation status were identified as independent prognostic factors. Conclusions: Our preliminary results showed that GSTM1-null genotype was associated with shorter survival.

Myeloperoxidase G-463A polymorphism and risk of lung and prostate cancer in a Turkish population.

Myeloperoxidase (MPO) is a phase I enzyme that can bioactivate many specific procarcinogens, including polycyclic aromatic hydrocarbons and aromatic amines. The MPO gene contains a common single nucleotide polymorphism, for which the -463G>A substitution within the promoter region has been shown to reduce MPO expression and activity. We investigated the association between the MPO -463G>A polymorphism and lung and prostate cancer in a Turkish population. MPO genotypes in the study populations were determined using polymerase chain reaction-based restriction fragment length polymorphism assay. The allelic frequency was significantly different between the cases and controls for lung cancer (p=0.02), but not prostate cancer (p=0.30). No significant difference was noted between the lung and prostate cancer cases and control populations in terms of genotype distribution (p=0.07, p=0.53, respectively). Control groups of lung and prostate cancer were in Hardy-Weinberg equilibrium (p=0.87 and p=0.41, respectively). To determine the protective effect against lung cancer among individuals with the -463A allele, G/A and A/A genotypes were combined. Comparison of the G/G and G/A + A/A genotypes between the lung cancer cases and control groups showed a statistically significant relationship (p=0.032, OR=0.60, 95% CI 0.38-0.95). No gender-specific difference was found in terms of genotype distribution between the lung cancer patients and the controls (female, p=0.20; male, p=0.34). In the case of smokers, a difference in genotype distribution between the lung cancer patients and the controls was statistically significant (p=0.02), although this difference was not statistically significant for non-smokers (p=0.90). Overall, no statistically significant difference was found between the prostate cancer cases and the controls in terms of genotype combination (p=0.46, OR=0.83, 95% CI 0.51-1.36). Additionally, in smokers and non-smokers, no significant relationship was determined between the prostate cancer patients and the control population (p=0.21, p=0.91, respectively). These results suggest that the MPO -463A allele significantly contributes to a protective effect overall and in smokers against lung cancer.

An investigation of the relationship between SULT1A1 Arg213His polymorphism and lung cancer susceptibility in a Turkish population

Human sulfotransferase 1A1 (SULT1A1), the most expressed isoform of the phenol SULT1 subfamily, is an important member of sulfotransferase superfamily. A transition, G to A at position 638, in SULT1A1 gene, results in Arg213His change. This single nucleotide polymorphism reduces the activity and thermostability of SULT1A1 enzyme. Thus, in the present study the relationship between SULT1A1 Arg213His polymorphism and lung cancer was investigated. One hundred and six case and 271 control samples were studied using PCR‐RFLP. There was no significant difference in genotype and allele distribution between lung cancer and control populations (p = 0.07; p = 0.06, respectively). Compared with the SULT1A1*1/SULT1A1*1 genotype the variant SULT1A1 genotype (SULT1A1*1/SULT1A1*2 or SULT1A1*2/SULT1A1*2) was associated with a significantly increased lung cancer risk in cases (p = 0.027). In male populations, there was no significant difference between case and controls (p = 0.313). In female populations, however, this difference was found to be significant (p = 0.04). In smoker and non‐smoker populations, no significant relationship was evident between lung cancer and control population (p = 0.170, p = 0.065, respectively). Statistical analyses of histological types of lung cancer in comparison with the control individuals indicated a significant difference between SULT1A1 Arg213His polymorphism and SCC (p = 0.027) and other types of cancer (p = 0.037), except SMCC (p = 0.854). Copyright

Microsomal epoxide hydrolase polymorphisms.

Microsomal epoxide hydrolase plays a dual role in the activation and detoxification of carcinogenic compounds. Two polymorphic sites have been described in exons 3 and 4 of the microsomal epoxide hydrolase gene that change tyrosine residue 113 to histidine (Tyr113His) and histidine 139 to arginine (His139Arg), respectively. The exon 3 polymorphism reduces enzyme activity by approximately 50%, whereas the exon 4 polymorphism causes a 25% increase in activity. In the present study, the distribution of these polymorphisms in a Turkish population including 625 unrelated healthy individuals was examined using a PCR-RFLP method. The observed genotype frequencies of microsomal epoxide hydrolase exon 3 were 54, 38 and 8% for Tyr113Tyr, Tyr113His and His113His, respectively. Exon 4 genotype frequencies were found to be 69, 29 and 2% for His139His, His139Arg and Arg139Arg, respectively.

No association of polymorphisms in the glutathione S-transferase genes with pre-eclampsia, eclampsia and HELLP syndrome in a Turkish population

Aim: There is substantial evidence that genetic factors play a role in pre‐eclampsia. The aim of this study was to determine whether genetic variability in the encoding of genes for glutathione S‐transferase M1 (GSTM1) and glutathione S‐transferase T1 (GSTT1) contributes to individual differences in susceptibility to pre‐eclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome).

Association between the soluble epoxide hydrolase gene and preeclampsia

ABSTRACT Objective: In this study the association between K55R polymorphism, methylation level of the EPHX2 promoter region, and PE was investigated in 520 individuals including 260 PE patients and 260 healthy pregnant women. Methods: K55R polymorphism and methylation level of the EPHX2 promoter were determined by the real-time PCR using double-dye hydrolysis probes and methylation-sensitive high-resolution melting analysis, respectively. Results: The presence of the K55R polymorphism was significantly higher in cases (28.1%) than controls (17.3%), and was associated with increased risk of PE (OR: 1.86; 95% CI: 1.09–2.63). Methylation levels of the EPHX2 promoter region in cases were significantly lower than controls. A 2.83 times increased PE risk was observed in pregnant women with EPHX2 promoter methylation levels of <25% (OR: 2.83; 95% CI: 1.15–6.91). Conclusion: In conclusion, hypomethylation of the promoter region of EPHX2 and K55R polymorphism were associated with significant increased risk of PE. sEH enzyme may play a role in the pathogenesis of PE by contributing to reduction of the vasodilatator, anti-hypertensive, and anti-inflammatory effects of EETs by rapid degradation of these molecules.

Investigation of the Association between Genetic Polymorphism of Microsomal Epoxide Hydrolase and Primary Brain Tumor Incidence

mEH is a critical biotransformation enzyme that catalyzes the conversion of xenobiotic epoxide substrates into more polar diol metabolites: it is also capable of inactivating a large number of structurally different molecules. Two polymorphisms affecting enzyme activity have been described in the exon 3 and 4 of the mEH gene. The hypothesis of this study is that inherent genetic susceptibility to a primary brain tumor is associated with mEH gene polymorphisms. The polymorphisms of the mEH gene were determined with PCR-RFLP techniques and 255 Turkish individuals. Our results indicate that the frequency of the mEH exon 4 polymorphism (in controls) is significantly higher than that of primary brain tumor patients (OR = 1.8, 95% CI = 1.0–3.4). This report, however, failed to demonstrate a significant association between mEH exon 3 polymorphism and primary brain tumor susceptibility in this population. Analysis of patients by both histological types of primary brain tumor and gene variants showed no association, although analysis of family history of cancer between cases and controls showed a statistically significant association (χ 2 = 7.0, P = 0.01). Our results marginally support the hypothesis that genetic susceptibility to brain tumors may be associated with mEPHX gene polymorphisms.