The overall goal of the current proposal is to understand, further, the role of altered regulation and patterns of DNA methylation in the progression of colon cancer. The investigators have described incremental increases in activity of the enzyme, DNA methyltransferase (DNA-MTase), from the earliest to the latest progression stage of colon neoplasia. In this setting they have also defined, for multiple genes important to the tumorigenic process, hypermethylation of promoter region CpG islands associated with loss of gene transcription. Both events, increased DNA- MTase and hypermethylation of selected genes, also increase in colon mucosa as a function of age. The current studies seek to determine, further, how, in colon mucosa, the above alterations in DNA methylation regulation and patterns may be linked to one another during aging and in predisposition states for colon tumors. The cell types responsible for these events during tumor progression will be elucidated. A colon tumor progression model for gene hypermethylation events will be constructed. For specific genes, the role of inactivation in colon tumorigenesis will be assessed. Finally, the investigators seek to determine whether increases or decreases in DNA-MTase activity directly influence the rate, and extent, of colon tumor progression and whether this enzyme may constitute a legitimate target for colon cancer prevention and early intervention strategies.
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