GENETIC DETERMINATES OF HUMAN COLON NEOPLASIA

Case Western Reserve University, Cleveland OH

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Abstract

Dr. Georgia Wiesner is a junior faculty member in the Department of Genetics at Case Western Reserve University (CWRU) who is uniquely qualified for a K23 career development award. She has dual training in Medical Genetics and Internal Medicine and has a long term goal of conducting patient-oriented research in cancer susceptibility. Dr. Wiesner is currently the principal Geneticist on a research project with her mentor, Dr. Sanford Markowitz, which is aimed at establishing a patient-based family resource of kindreds with colon cancer and colon adenomatous polyps in order to identify new genes that cause colon neoplasia. Along with Dr. Robert Elston, co-mentor, Dr. Markowitz and his group will provide an outstanding research and educational environment that will allow Dr. Wiesner to advance toward her goal of independent translational research in genetics and molecular biology. The long range objectives of this proposal are to identify the gene or genes in the American population that cause susceptibility for colon cancer or colon adenomatous polyps. This will be done using the affected sibling pair methodology on a unique cohort of kindreds that Dr. Wiesner is currently establishing at CWRU. These families have at least one pair of siblings who have both been diagnosed with colon cancer and/or adenomatous polyps. The notion that certain genetic loci are linked to the development of colon neoplasms is a central concept of carcinogenesis and there is compelling evidence that a significant fraction of common forms of colon cancer are caused by unknown genes that increase an individuals life-time risk for colon cancer development. The specific aims of the proposal are: 1. To ascertain and collect DNA from 300 sibling pairs who are both affected with colon cancer and/or adenomatous polyps. 2. To identify, and exclude from linkage analysis, kindreds with known syndromes that have been linked to early onset forms of inherited colon cancer. 3. To test whether neoplasia in the study analysis population of affected sibling pairs demonstrates linkage to any of the candidate gene loci APC, COX2, sPLA2, and DNMT, or NAT1/2 for which colon neoplasia susceptibility variants have been identified in murine models or in restricted human populations and 4. To employ a set of 350 polymorphic markers to conduct a complete scan of the genome to identify new genes that are associated with susceptibility for cancer or colon polyps in these sibships.