Microsatellite instability and aberrant methylation in gastrointestinal cancer and its application to molecular target therapy

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Microsatellite instability (MSI) caused by the defect of DNA mismatch repair genes plays a role in Hereditary non-polyposis colorectal cancer (HNPCC). MSI also plays a role in sporadic colorectal and gastric cancers. In the current study, we identified the genes inactivated by MSI and/or aberrant methylation in gastrointestinal cancers, and examined their role in development and progression of gastrointestinal cancers. DNA methylation is an epigenetic change that can be reversed by methyltransferase inhibitors. We examine basic research that leads to development of molecular target therapy in gastrointestinal cancers. We examined the relationship between MSI and methylation changes in gastrointestinal cancers. We found that 80% of sporadic colorectal cancers with MSI were caused by epigenetic inactivation of hMLH1 associated with CpG island methylator phenotype (CIMP). CIMP positive colorectal cancers showed distinct genetic and epigenetic features including high frequency of methylation of p16 and mutations of BRAF, and low frequency of p53 mutations. These results indicated that CIMP positive colorectal cancer arises in a different pathway compared to HNPCC. We also showed that epigenetic inactivation of the regulators of WNT and Ras play a role in activation of WNT and Ras signaling pathways. Inhibition of DNA methylation by a methyltransferase inhibitor results in induction of pro-apoptotic genes, which results in enhancement of apoptosis in cancer cells. Our results indicated that DNA methylation can be a molecular target for therapy of gastrointestinal cancers.