Promoter methylation and Ile105val polymorphism of GSTP1 gene in the modulation of colorectal cancer risk in ethnic Kashmiri population.

Abstract

Glutathione-S-transferases (GSTs) are the most important phase II enzymes of the xenobiotic pathway responsible for the detoxification of carcinogens. GSTP1 gene polymorphisms are mostly associated with a lack or an alteration of enzymatic activity toward several substrates thus resulting in increased cancer susceptibility. GSTP1 promoter methylation is also frequently associated with tumor development or poor prognosis in a wide range of tumors. In this study, we examined the role of genetic polymorphism and promoter methylation of GSTP1 gene in the context of modulation of risk of colorectal cancer (CRC) in Kashmiri population. This study used tissue tumor samples (114) and blood samples from (160) patients with CRC and 200 blood samples from healthy donors. GSTP1 polymorphism was studied using polymerase chain reaction (PCR)-restriction fragment length polymorphism and methylation using methylation-specific PCR. There was no significant association between GSTP1 I105V genotypes and the CRC (P>0.05). However, we found a significant association of the Val/Val variant genotype with the dwelling and smoking status (P-value < 0.05). Overall, the homozygous variant Val/Val genotype was associated with a modestly elevated risk for CRC (OR = 1.57; 95% CI = 0.67-3.57). Methyl-specific-PCR analysis revealed 25.4% methylation of the GSTP1 promoter in CRC cases and was not found to be statistically significantly associated with clinicopathological parameters of the CRC cases (P>0.05). Also, no significant associations of any of the three genotypes with promoter hypermethylation were observed. We conclude that promoter hypermethylation in homozygous GSTP1 mutants did not elevate the risk of CRC in Kashmiri population.