Mechanisms of inactivation of the CDKN2A gene and its role in gastric carcinogenesis

The goal of this project is to investigate genetic events in tumor progression by determining whether preneoplastic gastric cancer lesions as well as gastric adenocarcinomas have loss of CDKN2A (p16) through either loss of heterozygosity or hypermethylation of the promoter region of the gene. Furthermore, we want to compare these findings to clinicopathological features such as grade and stage of the tumor, as well as ethnicity and gender of the patients, and prognosis.; The CDKN2A gene encodes a cyclin dependent kinase inhibitor, p16, which promotes cell cycle arrest. Methylation of the promoter region of the gene transcriptionally inactivates the gene. We have analyzed the methylation status of the promoter region of the CDKN2A gene in gastric adenocarcinomas using methylation specific PCR (MSP). In addition, we used microsatellite markers near the CDKN2A gene to detect allelic imbalance (AI). We also examined the tumors by immunohistochemistry (IHC) for p16 expression. Of 102 gastric adenocarcinomas analyzed by IHC, 30 cases (29%) were negative for p16 protein. Sixteen (53%) of the 30 had methylation of the promoter region of the CDKN2A gene. Patients whose tumors showed CDKN2A promoter methylation or Al near the gene showed significantly poorer survival (P = 0.005).; We also analyzed the mechanisms of CDKN2A gene inactivation with Epstein-Barr virus and Helicobacter pylori status in gastric adenocarcinomas. We found significant associations between the presence of Epstein-Barr virus and methylation of the CDKN2A promoter region (P < 0.001) and absence of p16 by immunohistochemistry (P < 0.001). However, there were no significant associations seen with H. pylori status and mechanisms of CDKN2A inactivation by promoter methylation (P = 0.365) or allelic imbalance (P = 0.618).; Finally, we investigated whether premalignant precursors of gastric cancer, specifically type I intestinal metaplasias, also have methylation of the CDKN2A gene promoter region. Analysis showed 38.5% of 13 cases of type I intestinal metaplasia that were adjacent to tumors with CDKN2A promoter methylation demonstrated CDKN2A promoter region methylation.; This study reveals that inactivation of CDKN2A is an early event in the development of some gastric cancers. Such findings contribute to our understanding of the genetic events that contribute to tumor cell proliferation, and this understanding may lead to individualization of therapeutic strategies.