Genetic polymorphism of drug metabolizing enzymes (CYP2E1, GSTP1) and susceptibility to bladder cancer in North India (original) (raw)
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European Urology, 2005
Objective: Glutathione-S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens. We examined the association of the GST gene polymorphism with sporadic bladder cancer patients in Northern India. Material and methods: The study constituted of 106 bladder cancer cases and 370 age-matched controls. The GSTT1 and GSTM1 null genotypes were identified by multiplex PCR and GSTP1313 A/G by Polymerase Chain Reaction/Restriction Fragment Length Polymorphism method (PCR/RFLP). Results: We observed non-significant association in null alleles of the GSTM1 (p = 0.611, OR = 1.12, 95% CI = 0.72-1.74 and GSTT1 (p = 0.135, OR = 1.45, 95% CI = 0.89-2.37) with risk of bladder cancer. However, the G/G genotype of the GSTP1 gene polymorphism was highly significant when compared to controls (p = 0.000, OR = 7.12, 95% CI = 3.14-16.16). The combined analysis of the three risk genotypes demonstrated further increase in the risk of bladder cancer (p = 0.000, OR = 7.29 95% CI = 2.81-18.93). Conclusion: Our study demonstrated that GSTP1313 G/G polymorphism is a strong predisposing risk factor for bladder cancer. Combination of three GST genotypes association exhibiting gene-gene interaction further substantiates the increased risk of bladder cancer. #
Urologic Oncology, 2013
The glutathione-S-transferases (GSTs) comprise a class of enzymes that detoxify carcinogenic compounds by conjugating glutathione to facilitate their removal. Polymorphisms in GSTM1, GSTT1, and GSTP1 genes have been related to risk for bladder cancer. Studies focusing on GSTs gene variants relationship with the risk of bladder cancer have produced conflicting and inconsistent results. We examine the association between genetic polymorphism of glutathione S-transferase P1, GSTM1, GSTT1 genes and development of bladder transitional cell carcinoma (TCC). The study population consisted of 166 histologically confirmed male bladder TCC cases and 332 healthy male controls. Genotyping was done using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method and also investigated combined gene interactions. The GSTP1 Val/Val genotype was significantly associated with bladder cancer (OR 4.32, 95% CI: 2.64-6.34), whereas the association observed for GSTM1 null (OR 1.32, 95% CI: 0.82-2.62; P 0.67) and GSTT1 null genotype (OR 1.18, 95% CI: 0.79-1.67; P 0.74) did not reach statistical significance. There was a significant multiple interaction between GSTM1, GSTT1, and GSTP1 genotypes in risk of bladder cancer (P for interaction 0.02). The risk associated with the concurrent presence of GSTM1 positive and GSTP1 Ile/Val or Val/Val (OR 3.71, 95% CI: 2.34-5.54) and GSTT1 positive and GSTP1 Ile/Val or Val/Val (OR 2.66, 95% CI: 1.54-4.72) was statistically significant. Patients carrying GSTP1 Val/Val genotype were at increased risk for developing high-grade (OR 7.68, 95% CI: 4.73-19.25) and muscle invasive (OR 10.67, 95% CI: 6.34-21.75) bladder cancer. High risk for bladder TCC also was observed with respect to combined GSTT1 null/GSTP1 Ile/Val or Val/Val (OR 4.76, 95% CI: 2.68-18.72) and GSTM1 null/GSTT1 null/GSTP1 Ile/Val or Val/Val (OR 6.42, 95% CI: 4.76-14.72) genotype variant. This study suggests that the GSTP1 polymorphism and its combination with GSTM1, and GSTT1 may be associated with bladder cancer susceptibility in the Iranian population. Further confirmation in large population-based studies is needed.
Archives of Toxicology, 2001
We investigated the effect of the GSTM1 and GSTT1 null genotypes, and GSTP1 313 A/G polymorphism on bladder cancer susceptibility in a case control study of 121 bladder cancer patients, and 121 age- and sex-matched controls of the Turkish population. The adjusted odds ratio for age, sex, and smoking status is 1.94 [95% confidence intervals (CI) 1.15–3.26] for the GSTM1 null genotype, and 1.75 (95% CI 1.03–2.99) for the GSTP1 313 A/G or G/G genotypes. GSTT1 was shown not to be associated with bladder cancer. Combination of the two high-risk genotypes, GSTM1 null and GSTP1 313 A/G or G/G, revealed that the risk increases to 3.91-fold (95% CI 1.88–8.13) compared with the combination of the low-risk genotypes of these loci. In individuals with the combined risk factors of cigarette smoking and the GSTM1 null genotype, the risk of bladder cancer is 2.81 times (95% CI 1.23–6.35) that of persons who both carry the GSTM1-present genotype and do not smoke. Similarly, the risk is 2.38-fold (95% CI 1.12–4.95) for the combined GSTP1 313 A/G and G/G genotypes and smoking. These findings support the role for the GSTM1 null and the GSTP1 313 AG or GG genotypes in the development of bladder cancer. Furthermore, gene-gene (GSTM1-GSTP1) and gene-environment (GSTM1-smoking, GSTP1-smoking) interactions increase this risk substantially.
Polymorphisms in drug-metabolizing enzymes as modifiers of cancer risk
Clinical chemistry, 1995
The identification of low-penetrance genes, the polymorphisms of which increase an individual's risk of developing cancer, are likely to be extremely important in the general population. In this report we analyzed two genes involved in detoxification. In a number of loci, we identified polymorphic variation correlating with the expression of the gene product. We analyzed two such loci, the cytochrome P-450 gene CYP2D6 and the N-acetyltransferase 2 (NAT2) genes, in patients with bladder and colon cancer, respectively. We observed no statistically significant associations between the control and cancer populations; however, there was a small increase in heterozygote number in bladder cancer.
2018
The central event in cancer development is loss of genomic integrity which itself probably initiates from the alteration of genomic DNA by exogenous or endogenous carcinogens. All humans are exposed to various environmental and occupational sources of genotoxic compounds and radiations which may act as carcinogens. Genetic factors are thought to play a central role in determining individual susceptibility to carcinogens. Urinary bladder cancer (UBC) is the most common malignancy of the urinary tract. In this review, the literature investigating the relationship between genetic polymorphisms of drug metabolizing genes and the risk of UBC are summarised. We have thoroughly reviewed the DNA polymorphism studies on GSTM1, GSTP1, GSTT1, GSTM3, GSTA1, NAT1, NAT2, SULT, UGT, MPO, COMT, MnSOD, GPX1 and ADH3 genes in relation with UBC. Overall, it appears that genetic polymorphisms in the drug detoxification genes play an important role in determining susceptibility to UBC.
Objective To investigate the association between Active tobacco smoking and human glutathione s transferease omega rs4925 polymorphisms in patient with bladder cancer at Baghdad city. Methods A total of histopathologically confirmed 41 bladder cancer patients and 41 age matched apparently healthy controls were recruited from February 2014 to September 2014 in a case control study conducted in Department of Chemistry and Biochemistryand DNA Research and Training Center, Al-Nahrain University.Genotyping of the GSTO1 Ala140Asp polymorphism was evaluate using a polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) method. The odds ratio (OR) and 95% confidence interval (CI) were calculated as a measure of the combined effect of cigarette smoking and the GSTO1 Ala140Asp polymorphism on bladder cancer risk. Result it was founded that patients with the GSTO1 Ala/Asp and Asp/Asp genotype have no significantly increase bladder cancer risk (OR 1.66 ;95% CI =0.6834 - 4.0591). A statistically highly significant increased the bladder cancer risk was also found in ever smoker with the GSTO1 (Alal/Ala) (OR =9.6 ;95% CI=0.6834 - 4.0591) and (Ala/Asp +Asp/Asp) (OR =8 ;95% CI=2.18- 29.24) compared with never smoker Ala/Ala genotype Conclusion The study suggest that smokers having GSTO1 Ala/140Asp polymorphism could play an important role as risk factor for the development with bladder cancer.
International Urology and Nephrology, 2009
Genetic differences in the metabolism of xenobiotics have recently been suggested as modifiers of individual susceptibility to bladder cancer (BC). The objective of this study was to investigate the relationship between bladder tumor and variants of cytochrome p450 1A2 (CYP1A2) 734 C ? A, cytochrome p450 2D6 (CYP2D6) 1934 G ? A, glutathione S-transferase M1, (GSTM1 null), glutathione S-transferase T1 (GSTT1 null), and glutathione S-transferase P1 (GSTP1) I105 V. We investigated the distribution of these polymorphisms in 135 BC patients and in 128 age and sex-matched cancerfree controls. The polymorphisms were analyzed using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay and the multiplex PCR method. Genotype and allele frequencies and their associations with BC risk, demographic factors, smoking status, and tumor stage were investigated. The prevalence of GSTT1 null genotype in cases was 23%, compared with 7% in the control group (OR = 3.94, 95% CI = 1.70-9.38, P = 0.001). There was no association between the studied polymorphisms of CYP1A2, CYP2D6, GSTM1, and GSTP1 genes and BC. There was an association between smoking status and BC. These data seem to indicate that GSTT1 gene polymorphism may be associated with BC in the Turkish population studied. Further studies will be needed to clarify the role of such variation in determining susceptibility to BC.
Cancer research, 1996
Foreign compound-metabolizing enzymes may modify the risk of chemically induced cancer. We wanted to examine enzymes with putative relevance in urinary bladder cancer using molecular genetic analyses of heritably polymorphic enzymes. Arylamine N-acetyltransferase (NAT2); glutathione S-transferases (GSTs) M1 and T1; microsomal epoxide hydrolase; and cytochrome P-450 enzymes (CYP) 1A1, 2C19, 2D6, and 2E1 were analyzed in 374 cases and in 373 controls in a hospital-based case-control study in Berlin. Slow acetylation was a significant risk factor in heavy smokers [odds ratio (OR), 2.7; 95% confidence interval (CI), 1.0-7.4], with the greatest risk noted for the allele NAT2*5B. GSTM1 deficiency was a risk factor independent of smoking and occupation (OR, 1.6; CI, 1.2-2.2). GSTT1 was associated with cancer risk in the nonsmoker subgroup (OR, 2.6; CI, 1.1-6.0). The two amino acid polymorphisms that are known in microsomal epoxide hydrolase were not associated with bladder cancer risk. CYP...
Glutathione S-transferase M1 gene polymorphism in bladder cancer patients
Cancer Genetics and Cytogenetics, 2001
The glutathione S-transferase M1 ( GSTM1 ) gene is polymorphic in humans, and the deficiency in enzyme activity of GSTM1 is caused by the inherited homozygous absence of the GSTM1 gene, or the "null" genotype ( GSTM1 , 0/0). The increased risk of bladder cancer has been shown to correspond with this gene defect. No reports, however, have been found in the literature regarding GSTM1 gene deficiency with superficial and invasive bladder cancer. In this study, we examined the association of the GSTM1 -null genotype with superficial and invasive bladder cancer. Using a polymerase chain reaction (PCR)-based method, we examined the frequency of the GSTM1 gene defect in Turkish patients with superficial bladder cancer ( N ϭ 61), invasive bladder cancer ( N ϭ 42), and control subjects ( N ϭ 202) who had no history of cancer. The GSTM1 null genotype was observed in 34.7% of the control subjects and in 54.3% of total bladder cancer patients (OR: 2.246; 95% CI: 1.384-3.645, P : 0.00094). In other words, the presence of the GSTM1 -null genotype significantly increased the risk of bladder cancer development. Among invasive bladder cancers, the frequency of the GSTM1 -null genotype was 64.3% (OR: 0.294, 95% CI: 0.147-0.590, P : 0.0003). This was also significantly higher than control subjects, indicating that patients carrying this genotype were at increased risk for developing invasive bladder cancer. This relationship was not statistically significant in the superficial bladder cancer group (OR: 0.585, 95% CI: 0.327-1.045, P : 0.06). Our results indicate that GSTM1 gene polymorphism should be considered as an important risk modifier in the development of bladder cancer and might be used as a predictive marker for invasive bladder cancer.