Activation or mutation of cellular proto-oncogenes may be important events in tumor initiation, promotion and/or progression. The main goals of the studies presented in this proposal are to assess the expression of oncogene products, in particular, c-ras and c-myc in fresh tissue from human colon polyps, primary colon tumors and in metastatic lesions of these tumors, to determine if abnormal expression of these proto-oncogenes correlates with any of the stages of tumor development. The expression of activated c-ras proto-oncogenes (as determined by transfection assays) has been implicated in a variety of tumors. The proto-oncogenes of the myc family are amplified in many malignancies, sometimes at specific stages and indicative of prognosis. In some tumor cells, both a c-myc and c-ras proto-oncogene are aberrantly expressed. With the availability of fresh human tumor tissues at M.D. Anderson Hospital and Tumor Institute, the hypothesis that aberrant expression of one or both of these oncogenes correlates with some of the stages of colon malignancies will be tested. Colon tumors are a particularly good system for these studies because of familial polyposis coli (FPC) syndromes, in which slow development from polyp to carcinoma is inevitable barring surgical intervention. Thus, we will analyze as many types of polyps as can be obtained, including polyps from FPC patients, and malignant colorectal carcinomas of each of the Dukes' stages (in situ, B1, B2, C, D, and metastases to different organs). This study focuses on the protein products of these oncogenes, including determining the prevalence of mutated c-ras proteins, and immunoperoxidase studies onfixed tissue specimens to examine individual cells within the tumor, comparing them to adjacent normal tissues. The latter studies will be performed in collaboration with a member of the Pathology Department of this Institution. Thus, this study will represent the first to comprehensively assess the proto-oncogene products in fresh hauman tissue. Also included in this study are collaborating efforts with members of the Institution on the cytogenetics of the tumor cells as well as expression of mRNA and oncogene structure. The data obtained should be useful in understanding the mechanism(s) by which aberrant expression of c-ras genes may participate in tumorigenesis.
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