Role of DNA Methylation in the Development of Diffuse-Type Gastric Cancer

Abstract

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.

Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer

“…Etiologic analysis has shown that individuals with H. pylorirelated gastritis, severe atrophy, and intestinal metaplasia are at high risk of developing intestinal type gastric cancers, which are often associated with metachronous gastric cancer development. On the other hand, individuals with H. pylori-related pangastritis and enlarged-fold gastritis, which are lesions without mucosal atrophy or intestinal metaplasia, are at increased risk of developing diffuse type gastric cancers (3). Surveillance of these high-risk patients using reliable and accurate predictive markers is important for reducing the incidence of gastric cancer and its mortality.…”

“…The list of genes aberrantly methylated in gastric cancer is growing and now includes genes involved in cell-cycle regulation, apoptosis, immune function, cell signaling, and tumor invasion and metastasis (3,5). In addition, aberrant DNA methylation is frequently observed in noncancerous gastric mucosa in H. pylori-infected patients, suggesting aberrant DNA methylation is an early step during gastric carcinogenesis (6,7).…”

Hereditary Diffuse Gastric Cancer: A Family Diagnosis and Treatment

“…This leads to abnormal morphogenesis and architecture of epithelial tissue, loss of cellular polarity and contact inhibition, unregulated growth, and invasion of adjacent tissue. 12,13 Approximately 50 distinct CDH1 mutations throughout the gene have been described. 2,11,13 In addition to mutations, DNA methylation of the CDH1 promoter has been observed and may completely deactivate the gene, decreasing expression of E-cadherin.…”

“…12,13 Approximately 50 distinct CDH1 mutations throughout the gene have been described. 2,11,13 In addition to mutations, DNA methylation of the CDH1 promoter has been observed and may completely deactivate the gene, decreasing expression of E-cadherin. 13 Another recent observation is that when E-cadherin expression is greatly decreased or absent, exon v6-containing CD44 isoforms are over-expressed.…”

“…14 Between 25% and 50% of families that fit the International Gastric Cancer Linkage Consortium (IGCLC) criteria for HDGC will have autosomal dominant inherited germline CDH1 mutations, 2,4,6-11,13-15 and about 39% of HDGC patients carry a CDH1 gene mutation. 7,8,13 The penetrance is approximately 75%, 4,7,8 so the lifetime chance of an individual with a CDH1 mutation developing gastric cancer is great, and the risk increases with age. At age 20, the risk is estimated to be <1%, increasing to about 4% by age 30.…”