DNA mismatch repair (MMR) is critical for maintaining mitotic and meiotic genomic integrity. MMR malfunction causes cancer through a mutator phenotype called microsatellite instability (MSI) and failure to initiate apoptosis. Our previous studies revealed strong associations between MLH3 and both human and mouse colorectal cancer (CRC) susceptibility loci. Subsequently, MLH3 mutations were identified in atypical Hereditary Non-Polyposis Colon Cancer families, and CRCs demonstrated to harbor somatic MLH3 mutations. However, the relatively small number of families identified with MLH3 mutations to date has made ambiguous whether MLH3 deficiency is associated with MSI-L or MSI-H tumor subtypes, and what the precise spectrum of cancer susceptibility attributable to MLH3 mutations really is. In the Preliminary Data section, we present evidence Mlh3, like Mlhl, performs unique meiotic MMR functions in both male and female germ cells. Our hypothesis is that Mlh3 similarly performs unique mitotic MMR functions in mammals, but that the cancer susceptibility spectrum and MSI phenotype of MLH3 deficiency have not been clearly defined. We therefore propose the following Specific Aims:1. To determine the expression pattern of Mlh3 protein in mouse gastrointestinal, lymphoid and other epithelial tissues. Characterization of the precise temporal and spatial Mlh3 expression pattern will provide important clues to its biological functions and a foundation for further studies.2. To determine the Microsatellite Instability phenotype of Mlh3 / tissues. These analyses wilt help prioritize patients and tumors exhibiting MSI-Low or MSI-High subtypes for future MLH3 mutation analyses.3. To determine the cancer susceptibility spectrum of Mlh3 -/- and Mlh3-/-/Pms2-/- mice. Our hypothesis is that Mlh3-/- mice are susceptible to cancer. Cognizant of the alternative hypothesis Mlh3 and Pms2 are redundant in mitotic MMR, we will analyze cancer susceptibility in Mlh3-/-/Pms2-/- mice.4. To quantify the effect of Mlh3 deficiency on bowel carcinoma formation. We propose generating Mlh3-/- Apc A1638Nmice and performing quantitative analyses of bowel cancer formation. The onset and progression of tumor formation will make possible direct comparisons with other MMR genes in future studies.The comments in the CRITIQUE section were prepared by the reviewers assigned to this application and are provided without significant modification or editing by staff. The RESUME AND SUMMARY OF DISCUSSION section documents the final outcome of the evaluation by reviewers and is the basis for the assigned priority score
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