Methylation pattern of tumor suppressor genes in gastric adenocarcinoma: relationship with tumor invasion, lymph node metastasis and long term survival

• Grant number: 05/02709-0
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2005
• End date: October 31, 2007
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Ivete Bedin Prado
• Grantee: Ivete Bedin Prado
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

DNA methylation is an important epigenetic regulator of gene integrity and transcription. It is a chemical modification resulting in the addition of a methyl group (CH3) at a cytosine ring, in the sequence context 5 CG3, mostly at GpG islands. It has been recently reported to play a crucial role in tumor development and progression. Aberrant DNA hypermethylation has been demonstrated to result in loss of expression of a variety of genes in many tumors. Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. It is highly prevalent among us, with two thirds of cases been detected in developing countries. Better outcome is achieved at initial steps of lesion. Survival rate decreases with deeper local invasion, lymph node involvement and distant organ metastasis. Lymph node status is crucial to prognosis, both in early and advanced tumors, since it is known to be an independent prognostic factor for survival. As in other tumors, epigenetic silencing of tumor-related genes due to DNA methylation has been reported in gastric cancer, but results are controversial. Recently some of our group have reported epigenetic silencing of ADAM23 adhesion molecule in epithelial breast tumors. They showed also a higher degree of promoter hypermethylation in the more advanced grade tumors. The methylation pattern of gastric tumors in Brazilian people has not been studied. Moreover, as it is an early event and reversible, the study of DNA methylation pattern and the relationship between DNA methylation and prognosis is of utmost importance. The aim of this study is to analyze the methylation pattern of 10 genes, 6 of them not yet studied in gastric tumor, in tumoral and normal tissue of patients that underwent total gastrectomy for gastric adenocarcinoma in a consecutive 10 year period, according to gastric wall (T2 and T3) and lymph node (N0, N1 and N2) invasion, and to correlate the results with hystopathological parameters and long term survival. (AU)