MECHANISMS UNDERLYING GENETIC DEFECTS IN COLON CANCER

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DESCRIPTION (Applicant's Description): Dr. Eshleman received his M.D. and Ph.D. in Anatomy and Structural Biology for studies in muscle cell biology from the University of Pennsylvania. He completed residency, fellowship and postdoctoral training in the Department of Pathology at the same institution and joined the Department of Pathology at Case Western Reserve University in 1993 as a junior faculty member. His current research interest is cancer biology. He is now gaining new expertise in cancer and molecular biology, and in mutation research, which will enable him to develop an independent research program in this area. The goal of this proposal is to define the molecular mechanism and the role in human colon carcinogenesis of four newly defined, genetically distinct, colorectal cancer (CRC) "mutator" phenotypes. He has detected these mutator type CRC's by demonstrating in these cancers ten to 100 fold elevations of their rates of spontaneous hprt mutations. Three of these phenotypes are novel. These observations extend previous studies by his sponsors and collaborators which demonstrate that instability in DNA microsatellite sequences (RER phenotype) is present in both inherited and some sporadic CRC. They demonstrate that inherited, but not sporadic, RER cancers are due to defects in any of four genes involved in DNA base-base mismatch repair (MMR). Two of the distinct and novel phenotypes he defines are those in which RER CRCs are generated by defects not involving know MMR genes. Additionally, his studies demonstrate for the first time the existence of a novel mutator mechanism which induces sequence instability in non-RER CRCs. Analysis of these mutator phenotypes is now the focus of this proposal. He will characterize these novel phenotypes by determining the types of spontaneous mutations which occur in the hprt gene in these mutator backgrounds to identify the different classes of DNA repair systems which are absent in each of these mutator cells. He will determine the susceptibility of these deficient phenotypes to environmental agent induced mutations, which will provide insight into the interaction of environmental and genetic susceptibility in carcinogenesis. He will perform genetic complementation studies using both cell hybridization, and transfection, to determine how many underlying gene defects confer these phenotypes, and to provide initial data on the chromosomal locus of novel underlying defects. This information will enhance their understanding of carcinogenesis in familial and sporadic mutator CRC. Dr. Eshleman's current position at Case Western Reserve University provides an excellent opportunity to gain expertise in cancer and molecular biology and mutation research. His sponsors, Drs. Markowitz and Sedwick, are established investigators in these areas. The Departments of Pathology and Medicine and the Ireland Cancer Center will provide him with all of the necessary facilities for these studies, as well as a rich intellectual environment for academic, clinical, and research career development.