Role of DNA Methylation in the Development of Diffuse-Type Gastric Cancer
Role of DNA Methylation in the Development of Diffuse-Type Gastric Cancer
复制标题
DOI：
10.1159/000320453
复制
发表时间：
2011-01
期刊：
影响因子：
3.2
通讯作者：
Eiichiro Yamamoto;Hiromu Suzuki;H. Takamaru;Hiroyuki Yamamoto;M. Toyota;Y. Shinomura
中科院分区：
文献类型：
--
作者：
Eiichiro Yamamoto;Hiromu Suzuki;H. Takamaru;Hiroyuki Yamamoto;M. Toyota;Y. Shinomura
癌细胞表现出两种相反的甲基化异常：全基因组低甲基化和基因启动子高甲基化。 E-钙粘蛋白（CDH1）的下调在弥漫型胃癌的发生发展中起着关键作用，而DNA甲基化是该基因沉默的主要原因。遗传性弥漫性胃癌是由CDH1基因种系突变引起的，DNA甲基化经常作为第二次打击使该基因完全失活。在散发性弥漫型胃癌中，CDH1 的甲基化比该基因的突变更为普遍。 EB病毒（EBV）相关胃癌（EBV相关GC）的特点是多个基因同时甲基化，而弥漫型胃癌在EBV相关GC中常见。据报道，由幽门螺杆菌感染引起的全胃炎或肥大胃炎患者患弥漫型胃癌的风险增加。值得注意的是，肥大性胃炎患者的胃粘膜表现出CDH1高甲基化和全基因组低甲基化。这些数据表明，异常的 DNA 甲基化是弥漫型胃癌高危个体致癌的重要促进因素。
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.