P53 AND MDM2 IN THE DEVELOPMENT AND PROGRESSION OF BLADDER-CANCER

Objective: Earlier investigations have demonstrated that inactivation of the p53 tumor suppressor gene might play a role in the development and progression of bladder cancer. Complex formation with the MDM2 onc ogene product is one mechanism inactivating the p53 protein. Therefore , the MDM2 and the p53 protein were investigated to study potential in teractions in bladder cancer. Method: 200 archival bladder tissue spec imens from 92 patients were studied by immunohistochemistry using mono clonal antibodies DO-1 against p53 and IF2 against MDM2. Results: No s taining was observed for p53 or MDM2 in normal urothelium. Alterations of both genes were rare in dysplasia. p53 accumulation was observed i n 27-44% of the tumor stages examined. MDM2 overexpression increased f rom 18% in carcinoma in situ to 49% in T-1 tumors, but was present in only 22% of the advanced tumors. Alterations of both genes were more f requent in high-grade lesions. To investigate the prognostic impact of these alterations 61 patients with superficial bladder tumors were fo llowed for at least 2 years (mean 51 months). Multivariate analysis de monstrated that multifocal disease and p53 accumulation were significa ntly correlated with tumor progression (p = 0.0099 and 0.0135). MDM2 o verexpression alone had no prognostic significance. Patients with alte rations of both genes had a very high risk of tumor progression (p = 0 .0064). Conclusion: These results demonstrate a positive correlation b etween p53 accumulation and MDM2 overexpression in the progression of bladder cancer which may have prognostic value.