The goal of this program has been to elucidate mechanisms by which loss of DNA mismatch repair (MMR) function leads to genesis of human colon cancers with microsatellite instability (MSI), with particular emphasis on understanding MSI colon cancers that arise as sporadic non-familial disease (at a minimum, non-classical HNPCC). Based on extensive work accomplished during the initial funding period, this continuation will focus on understanding mechanisms that give rise to aberrant methylation of the hMLH1 promoter, and will exploit the specific DNA repair defect present in MSI colon cancers to develop new diagnostic and therapeutic strategies that target these tumors. There are 5 specific aims. First, to determine whether methylation of hMLH1 is due to an aberration that works in cis or in trans, and whether the underlying cellular defect is dominant or recessive. Second, to determine if the hMLH1 methylation is an initiation or progression event in colon cancer, and whether it occurs in tandem or independent of methylation of other genes. Third, to develop an assay for circulating methylated hMLH1 DNA as a diagnostic test for early detection of sporadic MSI colon cancer. Fourth, to determine what derivatives of ICR191 have optimal selectivity for killing MSI colon cancers both in cell culture and in vivo. Fifth, to develop a novel assay for recognizing individuals with germ line MMR mutations, by increasing genomic instability in their cultured lymphocytes that induces loss of the wild-type allele, thus generating MMR deficiency and MNNG resistence.
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