Establishment of epigenetic epidemiology

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(1) Epigenetic gene silencing through DNA methylation is one of the important steps in the mechanism underlying tumorigenesis, including of the stomach. Past lifestyle factors of cancer patients, such as intake of vegetables, are very important to affect gastric carcinogenesis. However, the relationship between DNA methylation and past dietary habits in cancer patients remains largely unknown. We analyzed the methylation states of the CDX2, BMP-2, p16. CACNA2D3, GATA-5, and estrogen receptor genes in 106 primary gastric cancers by methylation-specific PCR, and compared them with the past lifestyle of the patients. Methylation of CDX2 and BMP-2 was correlated with the decreased intake of green tea. Methylation of CACNA2D3 was inversely correlated with the physical activity. Thus, the past lifestyle could be important factors determining the methylation states of genes and the resultant aberrant expression of genes involved in carcinogenesis.(2) SOX transcription factors play critical ro … More les in cell fate determination, differentiation and proliferation. We previously reported that the SOX2 protein is expressed in normal gastric mucosae but down-regulated in some human gastric carcinomas. To clarify the roles of SOX2 in gastric carcinogenesis, we carried out functional characterization of SOX2 in gastric epithelial cell lines. Exogenous expression of SOX2 suppressed cell proliferation in gastric epithelial cells. Flow cytometry analysis revealed that SOX2-overexpressing cells exhibited cell cycle arrest and apoptosis. SOX2 hypermethylation signals were observed in some cultured and primary gastric cancers with no or weak SOX2 expression. Among the 52 patients with advanced gastric cancers, those with cancers showing SOX2 methylation had a significantly shorter survival time than those without this methylation. Hence, SOX2 plays important roles in growth inhibition through cell cycle arrest and apoptosis in gastric epithelial cells, and the loss of SOX2 expression may be related to gastric carcinogenesis and poor prognosis. Less