First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.
Digestion. 2011;83(4):241-9. doi: 10.1159/000320453. Epub 2011 Jan 27.
Cancer cells exhibit two opposing methylation abnormalities: genome-wide hypomethylation and gene promoter hypermethylation. Downregulation of E-cadherin (CDH1) plays a key role in the development of diffuse-type gastric cancer, and DNA methylation is a major cause of the gene's silencing. Hereditary diffuse gastric cancer is caused by germline mutation of CDH1 gene, and DNA methylation frequently serves as the second hit completely inactivating the gene. In sporadic diffuse-type gastric cancer, methylation of CDH1 is more prevalent than mutation of the gene. Epstein-Barr virus (EBV)-associated gastric carcinoma (EBV-associated GC) is characterized by concurrent methylation of multiple genes, and diffuse-type gastric cancer is frequently seen among EBV-associated GCs. Patients with pangastritis or enlarged-fold gastritis, which are both caused by Helicobacter pylori infection, reportedly have an increased risk for diffuse-type gastric cancer. Notably, the gastric mucosa of enlarged-fold gastritis patients exhibits CDH1 hypermethylation and genome-wide hypomethylation. These data suggest that aberrant DNA methylation is an essential promoter of carcinogenesis in individuals at high risk for diffuse-type gastric cancer.
全基因组低甲基化和基因启动子高甲基化。E-钙黏蛋白（CDH1）的下调在弥漫型胃癌的发展中起着关键作用，而 DNA 甲基化是导致基因沉默的主要原因。遗传性弥漫性胃癌是由 CDH1 基因突变引起的，而 DNA 甲基化经常作为完全失活基因的第二次打击。在散发性弥漫型胃癌中，CDH1 的甲基化比基因突变更为普遍。EB 病毒（EBV）相关胃癌（EBV-associated GC）的特征是多个基因的甲基化同时发生，而 EBV 相关 GC 中弥漫型胃癌较为常见。据报道，患有由幽门螺杆菌感染引起的全胃炎或大皱襞胃炎的患者患弥漫型胃癌的风险增加。值得注意的是，大皱襞胃炎患者的胃黏膜表现出 CDH1 高甲基化和全基因组低甲基化。这些数据表明，在弥漫型胃癌高危人群中，异常的 DNA 甲基化是致癌作用的重要启动子。
