Hypermethylation of tumor‐related genes in tunisian patients with gastric carcinoma: Clinical and biological significance

Abstract

Promoter hypermethylation is an alternative mechanism of gene silencing in cancers including gastric carcinoma (GC). Its affects genes with crucial functions as tumor suppressor. DNA methylation in the promoter of P16INK4a, DAPK, retinoic acid receptor β (RARβ2), RASSF1A, and CDH1 genes was investigated in 79 Tunisian patients with GC using methylation-specific PCR. The methylation frequencies vary from 31.6% for P16INK4a to 65.8% for RARβ2. Hypermethylation of DAPK and CDH1 was associated with tumor grade and age (P = 0.04 and 0.034) respectively, while hypermethylation of RASSF1A correlated with TNM stage (P = 0.027). The distribution of the methylated DNA at P16INK4a, DAPK, and CDH1 promoters were different in the intestinal and diffuse histotypes of GC according to TNM. Moreover, the survival rate of patients with P16INK4a methylated status was shorter than that of patients with the unmethylated status (P log rank = 0.009). On the other hand, the hypermethylation of RARβ2 correlated with COX-2 expression (P = 0.001). We showed that methylation of P16INK4a is predictive of poor prognosis and could be a useful marker. Moreover, the association between RARβ2 methylation and COX-2 expression suggests a functional link between these two proteins in gastric carcinogenesis.