Promoter methylation of tumor-related genes in gastric carcinogenesis

Abstract

Aberrant promoter methylation and subsequent silencing of cancer-related genes has been recognized as an important pathway involved in gastric carcinogenesis. In fact, several factors are believed to contribute to its induction in gastric epithelia, including aging, diet, chronic inflammation and infection of Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV). However, the underling mechanisms are not completely identified, despite the belief that increased expression or activity of DNA methyltransferases (DNMTs), or decreased demethylation activity may contribute to the excessive methylation. A great number of genes with promoter methylation have been observed in gastric cancer (GC), among which p16INK4A (p16), Mut L homologue 1 (MLH1), Epithelial-cadherin (E-cadherin), Runt-related transcription factor 3 (RUNX3), adenomatous polyposis coli (APC), O(6)-methylguanine-DNA methyltransferase (MGMT), Ras association domain family 1A (RASSF1A) and Death-associated protein kinase (DAPK) have been extensively studied. Unlike the distinct methylation characterization in single genes, methylation analysis of multiple genes may provide more information in risk prediction, early detection, prognosis assessment and chemotherapy choice for GC. Specifically, particular monitoring and screening should be performed on those over 45 years old, with precancerous gastric disease or infection of H. pylori or EBV. As an alternative to tumor tissues, methylation detection in patient sera or gastric washes may also be used in risk prediction and early detection. However, what still poses a great challenge as well as a puzzle is the determination of the very genes that should be used in methylation analysis. Because epigenetic alterations are normally reversible, drugs or chemical compounds with demethylating activity, such as 5-aza-2’-deoxycytidine (5-aza-dC) could be used in the treatment of patients with multiple gene methylation. In view of the adverse effects of 5-aza-dC, DNMT-targeted strategy has been proposed and may prove to be more effective than demethylating agents.