Promoter methylation and gene polymorphism are two independent events in regulation of GSTP1 gene expression

Abstract

Breast carcinogenesis is a multistep process, involving both genetic and epigenetic modification process of genes, involved in diverse pathways ranging from DNA repair to metabolic processes. This study was undertaken to assess the role of promoter methylation of GSTP1 gene, a member of glutathione-S-transferase family of enzymes, in relation to its expression, polymorphism, and clinicopathological parameters. Tissue samples were taken from breast cancer patients and paired with their normal adjacent tissues. A total of 51 subjects were studied, in which the frequency of promoter methylation in cancerous tissue was 37.25% as against 11% in the normal tissues (p ≤ 0.001). The hypermethylated status of the gene was significantly associated with the loss of the protein expression (r = −0.449, p = 0.001, odds ratio = 7.42, 95% confidence interval = 2.05-26.92). Furthermore, when compared with the clinical parameters, the significant association was found between the promoter hypermethylation and lymph node metastasis (p ≤ 0.001), tumor stage (p = 0.039), tumor grade (p = 0.028), estrogen receptor status (p = 0.018), and progesterone receptor status (p = 0.046). Our study is the first of its kind in Kashmiri population, which indicates that GSTP1 shows aberrant methylation pattern in the breast cancer with the consequent loss in the protein expression. Furthermore, it also shows that the gene polymorphism (Ile105Val) at codon 105 is not related to the promoter methylation and two are the independent events in breast cancer development.

Methylation of Glutathione-S-Transferase P1 Promotor in Egyptian Females with Breast Cancer

“…In accordance with our study, Wu et al, (2016) and Bhat et al, ( 2017) found that significantly high frequency of the promotor methylation of GSTP1 gene in breast cancer cases (p ≤ 0.001) when compared to the promotor hypermethylation profile of the normal tissues, and significantly hypermethylation of GSTP1 promotor region in breast cancer (BC) as compared with Begnin Breast Disease (BBD) and controls ( p=0.010. Similar findings were reported by Fang et al, (2015) meta-analysis.…”

“…They suggested that breast cancer patients with GSTP1 promotor hypermethylation may have a phenotype with more biological aggressiveness. The same observation was reported by Saxena et al, (2012) and Bhat et al, (2017) who showed significantly higher quantitative methylation levels in late stage compared to the early stage breast carcinoma (p = 0.014, p= 0.03; respectively). In addition Klajic et al, (2013) reported significant differences in methylation levels between the DCIS (Ductal carcinoma in situ) and invasive stage II tumors.…”

“…This result comes with findings of Callahan et al, (2016). However Bhat et al, (2017) found a correlation between GSTP1 increased methylation and histological grade and Fang et al, meta-analysis (2015) showed that the level of GSTP1 methylation increased significantly with the increase of tumor grades compared to low grade breast carcinomas. Small sample size and different research design may explain this difference.…”

“…However, the OR was 2.167 which denoted that postmenopausal ladies were twice at risk to have methylated GSTP1 promotor than premenopausal cases. Saxena et al, (2012), Miyake et al, (2013), Wu et al, (2016) and Bhat et al, (2017) found similar results. The current work also found that there was no statistical significant difference in methylation status between nullipara and multipara patients.…”

“…The relation between GSTP1 methylation and gene expression was shown in several studies as Bhat et al, (2017) stated that epigenetic silencing of the GSTP1 gene by CpG promotor hypermethylation is associated with the significant loss of the protein expression. This conclusion was also consistent with Fang et al, (2015) who clarified in their meta-analysis that GSTP1 gene promotor hypemethylation occurs more in breast cancer and thus may lead to cancer progression through inactivation of GSTP1 expression.…”