Published online Dec 7, 2015. doi: 10.3748/wjg.v21.i45.12742
Peer-review started: May 29, 2015
First decision: July 14, 2015
Revised: August 8, 2015
Accepted: October 13, 2015
Article in press: October 13, 2015
Published online: December 7, 2015
The sequence of events associated with the development of gastric cancer has been described as “the gastric precancerous cascade”. This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori (H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the most relevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and miRNAs in this context.
Core tip:Helicobacter pylori infection increases the risk of developing gastric cancer. Intestinal type gastric cancer is characterized by a histological cascade in which aberrant methylation of CpG islands and deregulation of microRNAs are observed. An exacerbated host response and bacterial virulence factors contribute to these epigenetic changes by enhancing DNA methyl transferase activity via nitric oxide production and silencing of tumor suppressor genes and miRNAs. Interestingly, methylated Reprimo DNA is detectable in blood samples and is potentially useful as an early detection marker. Finally, also the role of gamma glutamyl transpeptidase related mechanisms in the loss of the anti-apoptotic protein Survivin and gastric carcinogenesis is discussed.