Combined p53 and MDM2 biomarker analysis shows a unique pattern of expression associated with poor prognosis in patients with renal cell carcinoma undergoing radical nephrectomy

Abstract

To resolve much debated issues surrounding p53 function, expression and mutation in renal cell carcinoma (RCC), we performed the first study to simultaneously determine p53/MDM2 expression, TP53 mutational status (in p53-positive patients) and outcome in RCC. In total, 90 specimens obtained from patients with RCC, who were treated by radical nephrectomy, were analyzed by immunohistochemistry for p53 and MDM2 on a tissue microarray, and p53 was functionally and genetically analyzed in p53 positive samples. Outcome analysis was by the Kaplan-Meier method and univariate analysis was used to identify variables for subsequent multivariate analysis of correlations between clinical parameters and biomarker expression. Up-regulation of p53 in RCC is strongly linked with MDM2 up-regulation (P < 0.001). Increased coexpression of p53 and MDM2 identifies those patients with a significantly reduced disease-specific survival by univariate (P= 0.036) and Cox multiple regression analysis (P= 0.027; relative risk, 3.20). Functional (i.e. functional analysis of separated alleles in yeast) and genetic analysis of tumours with increased p53 expression shows that most patients (86%) retain wild-type p53. Coexpression of p53/MDM2 identifies a subset of patients with poor prognosis, despite all of them having organ-confined disease. Up-regulated p53 is typically wild-type and thus provides a mechanistic explanation for the association between p53 and MDM2 expression: up-regulated wild-type p53 likely promotes the observed MDM2 coexpression. The results obtained in the present study suggest that the p53 pathway is altered in a tissue/disease-specific manner and that therapeutic strategies targeting this pathway should be investigated to determine whether the tumour suppressive function of p53 can be rescued in RCC.