This proposal has three main goals: 1) To expand the collaborative role of The Johns Hopkins Bowel Tumor Working Group (BTWG) in the areas of joint projects and exchanges of tissue specimens from well-defined patient groups at different risk for colorectal neoplasia. 2) To expand our search for biomarkers that are relevant to development of colorectal neoplasia during the stages of evolution from normal-appearing mucosa to presence of the neoplasms. 3) To correlate the biomarkers with each other and with clinical and pathological findings. THe BTWG was formed in 1984 with support from institution funds. A major component of the BTWG is the Johns Hopkins Bowel Tumor Registry. This registry of patients and families began in 1973 as a Polyposis Registry and provides ready access to patients and families with different verified risks of colorectal carcinoma (e.g. adenomatous polyposis/Gardner's syndrome, nonpolyposis colorectal carcinoma syndromes, familial aggregates, and cases of sporadic colorectal carcinomas and adenomas). A variety of known and potential markers pertaining to colorectal neoplasms will be studied. Ornithine decarboxylase will be studied in crypt epithelium and neoplasms by determining enzyme activity, m-RNA levels, biosynthetic products (polyamines), and localization using immunohistochemistry. Epithelial proliferation indices will be derived from in vitro tritiated thymidine incorporation into DNA, flow cytometry, and autoradiographic and immunohistochemical localization. ras and myc transcripts and gene products will be localized by in situ hybridization and immunohistochemistry. Similarly, blood group antigen will be studied for expression, localization, and synthesis. Incidence and timing of ras gene mutation will be studied. Hypermethylation of the calcitronin gene, which has been found in colonic carcinoma cell lines, will be investigated in primary tumors and tissue culture. These markers will be correlated with each other and with the clinical and pathologic stages in evolution from normal-appearing colonic mucosa to neoplasia in patient groups with different risks. It is hoped that the role of the markers in the pathogenesis of colorectal neoplasia and their clinical applicability can be determined.
