EVALUATION OF GPX1 PRO198LEU POLYMORPHISM, GSTP1 EXPRESSION AND GENE PROMOTER METHYLATION IN MOROCCAN PATIENTS WITH BLADDER CANCER

Abstract

Bladder cancer (BC) is the third most common male malignancy in Morocco. The risk factors for developing BC are multiples including dietary conditions, environmental exposure and oxidative stress. Glutathione Peroxidase-1 (GPX1) and Glutathione S-Transferase Pi (GSTP1) are two key enzymes in cell detoxification process. GPX1 Pro198Leu polymorphism is associated with a decrease of enzyme activity and may contribute to BC susceptibility. Deregulated expression of GSTP1 enzyme was reported in various human tumors, also, epigenetic silencing of GSTP1 gene by aberrant promoter methylation has been shown to be involved in the molecular pathway for cancer development. In this study, we aimed to assess the presence of GPX1 Pro198Leu polymorphism and determine the expression status of GSTP1-in relation to its promoter methylation- in Moroccan population to evaluate their association with the risk of developing BC in Moroccan patients. Genotyping of GPX1 Pro198Leu polymorphism was carried out by Sanger sequencing. GSTP1 expression was assessed by immunohistochemistry, GSTP1 promoter methylation status was studied by Methylation Specifiq PCR method. No significant association between GPX1 Pro198Leu polymorphism and BC occurrence was found (Pro/Leu vs. Pro/Pro: p=0.425). For the analysis of Pro198Leu polymorphism and progression of BC, no association was observed neither for stages (Pro/Leu vs. Pro/Pro: p=0.500) nor grades (Pro/Leu vs. Pro/Pro: p=0.415). GSTP1 expression was strong in 23.33%, moderate in 60% and weak in 13.33% of BC cases. Variability of the expression does not correlate with high-grade cancer or invasive-stage (p˃0.05). No GSTP1 promoter methylation was detected in all cases. Our results showed that GPX1 Pro198Leu polymorphism and GSTP1 expression are not closely associated with the risk of BC in our population, suggesting that the effect of these biomarkers on BC development might be a result of a combination with other genetic and epigenetic alterations and/or non-genetic variables such as diet and lifestyle factors.