The Preventive Oncology Award (K07) will provide an excellent opportunity to become a cancer prevention researcher/educator to bridge the gap between basic cancer biology and epidemiology. Under the supervision of excellent academic scientists at Fred Hutchinson Cancer Research Center and University of Washington, this plan will provide training in human genetics and enhance career development in epidemiology. The training plan proposed involves four areas: a) coursework; b) teaching; c) participation in seminars; and c) research. A brief summary of the research proposal follows. There is a great deal of evidence supporting the potential for dietary and chemopreventive factors that can reduce the risk for colon cancer, a disease that is a leading cause of mortality and morbidity in the United States. Development and application of intermediate biomarkers that """"""""mark"""""""" or signal stages preceding the development of a malignant tumor are important. These biomarkers shorten the time and cost of testing chemopreventive regimens, as well as to help identify and monitor the cancer process. The proposed research involves investigating the potential of genetic alterations as intermediate biomarkers for human colorectal cancer. Colorectal tumors appear to arise and progress due to the accumulation of mutations in oncogenes and tumor suppressor genes. In considering genetic mutations as useful biomarkers for colorectal cancer chemoprevention studies, it is important that these events occur relatively early in the process of carcinogenesis; are differentially expressed in high risk vs. normal tissue; and are accurate for predicting the risk for cancer. The proposed research plan involves investigating the potential of APC, K- ras, and p53 mutations as intermediate biomarkers (singly or in combination) for human colorectal cancer by addressing the issues stated in the preceding paragraph. These genetic mutations were carefully chosen based on the stages when they occur and their prevalence during colorectal tumorigenesis. To address the first two issues, APC and K-ras mutations will be investigated in """"""""hyperproliferative"""""""", histologically normal mucosa surrounding neoplasms. To address the third issue, the differences and prevalence of the APC, K-ras and p53 mutations in adenomas from patients who have polyps recurrence will be compared to those that do not. Once these biomarkers have been characterized and validated, their potential application to chemoprevention studies can be considered.
| Maltzman, T; Knoll, K; Martinez, M E et al. (2001) Ki-ras proto-oncogene mutations in sporadic colorectal adenomas: relationship to histologic and clinical characteristics. Gastroenterology 121:302-9 |
| Iwamoto, M; Ahnen, D J; Franklin, W A et al. (2000) Expression of beta-catenin and full-length APC protein in normal and neoplastic colonic tissues. Carcinogenesis 21:1935-40 |
| Maltzman, T; Whittington, J; Driggers, L et al. (1997) AOM-induced mouse colon tumors do not express full-length APC protein. Carcinogenesis 18:2435-9 |
