HUMAN MUTATOR GENES AND THERAPEUTIC EFFICACY IN COLORECTAL CANCER

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Hereditary Non-Polyposis Colorectal (HNPCC) accounts for 6-10% of colorectal cancers and is primarily associated with germline alterations in the human mismatch repair (MMR) genes hMSH2 and hMLH1. Three other MMR genes [hMSH3, hMSH6 and hPMS2] have demonstrated MMR functions in vitro but are rarely altered in HNPCC. In addition to HNPCC, an average of 10-20% of sporadic tumors of all types manifest microsatellite instability (MCI) that is a hallmark of a human MMR defect. The human MMR genes are related to highly conserved families of MMR proteins identified from bacteria to man. We have developed the internationally recognized procedure(s) for the MMR-pathway leading to tumorigenesis. Moreover, we have discovered a novel signaling mechanism used by the MMR genes to direct repair and/or apoptosis. We propose to: 1.) determine which of the known MMR genes (Hmsh2, Hmsh3, MSH6, hMLH1 and hPMS2) are altered analysis, followed by direct exon sequencing, tissue Fluorescent in situ hybridization (FISH) and the development of other novel mutational detection schemes; II.) determine which of a combination of MMR-pathway genes are altered in MSI tumors in comparison to Aneuploid-Pathway tumors by: a.) sequence for p53, K-ras, TGFRII, IGF-RII, BAX, Tcf-4, beta-catinin, and chromosome 18q LOH; and b) IHC for APC, FHIT, p53, p21, Bcl2, PLA2g2s; III.) det4ermine the cellular consequences of exposures to cisplatinum, MNNG, CPT-11, 5-Fluorouracil and ionization radiation on genetically defined MMR defective cell, to be used as a predictor of therapeutic efficacy; and IV.) determine the functional consequences/processes associated with MMR signaling to downstream effectors leading to DNA repair and/or apoptosis in vitro and in vivo. These studies are straight-forward and should provide a database on the functional alterations of the human MMR genes if colorectal tumors as well as a firm foundation for diagnostic and therapeutic efficacy of MMR-Pathway tumors.