Elucidation, of the interacting mechanism between epigenetic and genetic alterations in gastrointestinal cancers and of the possible application to the clinic

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We have been studied molecular mechanisms of gastrointestinal carcinogenesis and 'cancer progression. We have been identified several genes whose mutation has a important role in carcinogenesis, including E2F-4 in colorectal and gastric cancer and ING1 in esophageal squamous cell cancer. Recently not only genetic, including mutations and deletions, but also epigenetic alterations are involved in many types of carcinogenesis. The most typical epigenetic alteration is the promoter hypermethylation, which causes the silencing of the gene. DNA methylation occurs preferentially within dense clusters of CpG sites know as CpG islands. Therefore reference is made to a CpG island methylator phenotype (CIMP). Most of our recent work was focused on this promoter methylation of multiple genes in gastrointestinal cancers, and we made tremendous, progress in this' field. We found that the important DNA repair gene MGMT (06-methylguanine DNA methyltransferase) is controlled of its expression by promo … More ter methylation, and the level of methylation is strongly related to the prognosis and chemoresistance of colorectal cancers (Clinical Cancer Research). Furthermore, we classified colorectal cancer by mutational status of KRAS and BRAF, and showed close correlation to the methylation status of the multiple promoter methylation in colorectal cancer (Journal of Clinical Oncology). More recently, we investigated the overall relationship between activation of RAS-RAF signaling pathway and global hypermethylation in a large panel of methylation markers that included both CIMP-related and unrelated loci. In addition, we found that aberrant DNA methylation is only a disease of older individuals with MSI-H but in associated with a subset of Lynch syndrome. Herein, we found that methylation of various epigenetic markers is not a random phenomenon but is clearly segregated with both KRAS and/or BRAF mutations. Thus, overall activation of RAS-RAF pathway associates with aberrant DNA methylation in both sporadic and hereditary colon cancers. We also investigate microRNA as a possible epigenetic role in gastrointestinal carcinogenesis. Less