Gastric cancer: MOLECULAR BIOLOGY Part 2

31 Mar

Helicobacter pyloriGenetics events further reinforced the observation that two different pathways exist in the intestinal and diffuse types of gastric cancer. Mutations of the p53 gene were essentially restricted to the intestinal type in the early phase but were involved in both types in the advanced stage. Loss of heterozygosity, mutations of the adenomatous polyposis coli and the ‘deleted in colon cancer’ genes, and amplification of the c-erbB-2 gene were frequently associated with intestinal-type gastric cancers but were seldom found in the diffuse type. Microsatellite instability was found in 64% of the diffuse type but only 17% of the intestinal type. Amplification of c-met and k-sam tyrosine kinase receptor genes, as well as overexpression of the EGF family, transforming growth factor-beta, platelet-derived growth factor, insulin-like growth factor-II and fibroblast growth factor, are frequently found in diffuse type carcinomas. The involvement of the cadherin gene, an invasion suppressor gene, took place at an early stage in the diffuse type. Decreased expression of E-cadherin has been found in most diffuse-type gastric cancer. Germ-line mutation of the E-cad-herin gene has been found in familial carcinoma of the stomach.
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The relationship between H pylori and molecular changes may be another way to study the role of H pylori in gastric carcinogenesis. Kuniyasu et al found that the degree of H pylori infection correlated with the level of human telom-erase RNA expression and telomerase positivity in 26 carcinoma tissues. Moss et al showed that apoptotic cells occurred in about 2.9% of epithelial cells in uninfected gastric tissue samples, located in the most superficial aspect of gastric glands. Apoptotic cells were found in 16.8% of infected gastric tissues throughout the depth of gastric glands, and the value fell to 3.1% after H pylori eradication. Similar results have been obtained by others. Accumulation of mutant p53 protein at the regenerating zone of gastric pits was significantly decreased in the H pylori-eradicated group compared with the noneradicated group. Downregulation of the E-cadherin protein has been shown to be significantly associated with H pylori infection in patients with normal gastric mucosa, gastritis, gastric ulcer and duodenal ulcer. Studies on whether eradication of H pylori results in reversion or halting of the molecular events is important both in the understanding of gastric carcinogenesis and in the management of patients.