ALTERED PATTERNS OF MDM2 AND TP53 EXPRESSION IN HUMAN BLADDER-CANCER

Background: The TP53 gene maps to the short arm of chromosome 17 (17p1 3.1) and encodes for a nuclear phosphoprotein of 53 kd (p53) involved in cell cycle control. The MDM2 gene is located on the long arm of chr omosome 12 (12q13-14), and it encodes for a nuclear protein (Mdm2) of 90 kd of molecular mass. Genetic alterations in the TP53 gene have bee n reported as frequent events in bladder cancer and are associated wit h disease progression. The MDM2 gene has been shown to be amplified an d overexpressed in sarcomas; however, these changes have not yet been analyzed in neoplastic lesions of the urinary bladder, Purpose: We und ertook the present study in order to determine the frequency of MDM2 a nd TP53 abnormalities in bladder tumors, as well as to examine the cli nical relevance of identifying their altered patterns of expression in patients affected with bladder cancer. Methods: We analyzed a cohort of 87 patients affected by bladder tumors. Altered patterns of express ion of Mdm2 proteins were determined using an immunohistochemical assa y with monoclonal antibody 2A10, and MDM2 gene amplifications mere stu died by Southern blotting. Mutant p53 proteins were identified using m onoclonal antibody PAb1801. The presence of intragenic mutations in th e TP53 gene were assessed utilizing single-strand conformation polymor phism and further characterized by sequencing. Associations were asses sed statistically by the two-tailed Fisher's exact test. Results: Twen ty-six of 87 cases had abnormally high levels of Mdm2 proteins; howeve r, only one case showed an MDM2 amplification. Thirty-six of 87 cases displayed p53 nuclear overexpression. Sixteen cases had abnormally hig h levels of both Mdm2 and p53 proteins. There was a strong statistical association between Mdm2 and p53 overexpression (Fisher's exact test: P = .018). Moreover, there was a striking association between Mdm2 ov erexpression and low-stage, low-grade bladder tumors (Fisher's exact t est: P = .0005). Conclusions: The results suggest that aberrant Mdm2 a nd p53 phenotypes are frequent events in bladder cancer and mag be inv olved in tumorigenesis or tumor progression in urothelial neoplasias. Implications: This study is the first to report altered patterns of MD M2 expression in human bladder tumors and demonstrates that aberrant M dm2 and p53 phenotypes may be important diagnostic and prognostic mark ers in patients affected by bladder cancer.