The major transformation-inducing genes found in human solid tumors are members of the ras family of cellular oncogenes. Although less than 10% of bladder carcinomas have activated ras genes, as demonstrated in the mouse 3T3 assay, we have found elevated ras p21 in all high-grade bladder carcinomas examined. In the proposed studies we shall extend the immunohistochemical analysis of p21 to a large cohort of patients with """"""""precancerous"""""""" and neoplastic bladder lesions, on whom we have extensive clinical follow-up. In these sudies we shall attempt to confirm preliminary work in which we define the pattern of p21 expression found in normal urothelium and correlated p21 expression with degree of atypia in dysplastic lesion and histologic grade in carcinomas. We shall determine at what stage in the histogenesis of invasive bladder carcinoma p21 expression is increased and if recurrent tumors and metastases evolve a population of tumor cells which express high levels of p21. Of particular importance will be studies correlating p21 expression with tumor grade, stage and clinical outcome. Using p21 expression as a phenotypic marker for malignant potential of urothelial cells, we shall attempt to identify that subgroup of patients with marked dysplasia and with low grade papillary carcinomas who are at high risk for the ultimate development of invasive carcinoma. Further, we shall assay p21 in urine cells to determine if this assay is a useful adjunct to conventional urine cytology in the diagnosis of urinary tract cancer. In biochemical studies of bladder cancer specimens, we shall determine if a specific ras gene is consistently expressed and perform quantitative and qualitative analysis of steady state mRNA levels for that specific ras gene. We shall determine whether a normal or altered p21 molecule is expressed in bladder tumors by analysis of the electrophoretic mobility of tumor p21 and by analysis of tumor DNA for ras gene mutations at amino acid positions 12 and 61. Further, we shall determine if increased expression of ras p21 is associated with ras gene amplification or a structural alteration of the ras gene in question. Therefore, in these studies we shall determine if ras p21 is a relevant tumor marker in the detection and prognosis of bladder cancer, as well as determining the specific mechanism of ras gene activation in this common human cancer.
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