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

• Published in: BJU international Vol. 109; no. 8; pp. 1250 - 1257
• Main Authors: Noon, Aidan P., Polański, Radosław, El‐Fert, Ashraf Y., Kalirai, Helen, Shawki, Howida, Campbell, Fiona, Dodson, Andy, Eccles, Richard M., Lloyd, Bryony H., Sibson, David R., Coupland, Sarah E., Lake, Sarah L., Parsons, Keith, Vlatković, Nikolina, Boyd, Mark T.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2012; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; biomarkers; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Carcinoma, Renal Cell - surgery; clear cell renal cell carcinoma; Disease Progression; DNA, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic; Genotype; Humans; Immunohistochemistry; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidney Neoplasms - surgery; Kidneys; Male; MDM2; MDM2 protein; Medical sciences; Middle Aged; Multivariate analysis; Mutation; Nephrectomy; Nephrology. Urinary tract diseases; p53; p53 protein; Polymerase Chain Reaction; Prognosis; Proto-Oncogene Proteins c-mdm2 - biosynthesis; Proto-Oncogene Proteins c-mdm2 - genetics; Radicals; renal cell carcinoma; Retrospective Studies; Studies; survival; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - genetics; Tumors of the urinary system; Young Adult; Nephrology; Prognosis; Biological marker; mdm2 Gene; Urology; p53; TP53 Gene; Nephrectomy; Surgery; Grawitz tumor; Pattern analysis; Protooncogene; Tumor suppressor gene; Kidney disease; Human; Urinary system disease; Mesonephroma; clear cell renal cell carcinoma; Biological indicator; Malignant tumor; Survival; Clear cell carcinoma; renal cell carcinoma; Treatment; C-Onc gene; Kidney cancer; MDM2; Cancer
• ISSN: 1464-4096; 1464-410X
• DOI: 10.1111/j.1464-410X.2011.10433.x

What's known on the subject? and What does the study add? Unlike most other cancers mutations of the p53 gene (TP53), typically indicated by increased p53 expression, are rare in renal cell carcinomas (RCC) and there is no evidence that mutation of TP53 is associated with outcome or treatment response. However, whilst TP53 mutations are not linked with outcome, p53 expression is as we show here. Our study is the first to demonstrate simultaneously that patients with increased p53 expression (significantly associated with MDM2 expression), have reduced disease specific survival even though the expressed p53 is rarely mutated. We therefore identify increased expression of wild‐type p53 and MDM2 in RCC as targets for future therapeutic approaches. OBJECTIVE •  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. PATIENTS AND METHODS •  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. RESULTS •  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. CONCLUSIONS •  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.