Value of p53 as a prognostic marker in histologic subtypes of renal cell carcinoma: a systematic analysis of primary and metastatic tumor tissue.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and follows an unpredictable disease course. To improve prognostication, a better understanding of critical genes associated with disease progression is required. The objective of this review was to focus attention on 2 such genes, p53 and murine double minute 2 (MDM2), and to provide a comprehensive summary and critical analysis of the literature regarding these genes in RCC. Information was compiled by searching the PubMed database for articles that were published or e-published up to April 1, 2009. Search terms included renal cancer, renal cell carcinoma, p53, and MDM2. Full articles and any supplementary data were examined; and, when appropriate, references were checked for additional material. All studies that described assessment of p53 and/or MDM2 in renal cancer were included. The authors concluded that increased p53 expression, but not p53 mutation, is associated with reduced overall survival/more rapid disease progression in RCC. There also was evidence that MDM2 up-regulation is associated with decreased disease-specific survival. Two features of RCC stood out as unusual and will require further investigation. First, increased p53 expression is tightly linked with increased MDM2 expression; and, second, patients who have tumors that display increased p53 and MDM2 expression may have the poorest overall survival. Because there was no evidence to support the conclusion that p53 mutation is associated with poorer survival, it seemed clear that increased p53 expression in RCC occurs independent of mutation. Further investigation of the mechanisms leading to increased p53/MDM2 expression in RCC may lead to improved prognostication and to the identification of novel therapeutic interventions.

p53 and MDM2 in renal cell carcinoma: biomarkers for disease progression and future therapeutic targets?

Outcome prediction for renal cell carcinoma: evaluation of prognostic factors for tumours divided according to histological subtype

p53 aberrations are the most common genetic alteration found in human tumours and this review summarizes the current understanding of the clinical significance of p53 abnormalities Immunohistochemical and molecular techniques can demonstrate alterations at the protein and gene level, respectively, but with a significant discordance between the findings of either technique The tumours evaluated in this review include cancers of the breast, lung, gastrointestinal tract, genitourinary tract, and others In most cases, only data on p53 protein are available and in each of these tumour types discrepant conclusions on the clinical value of p53 abnormalities as prognostic indicators have been reached The role of p53 in the context of anticancer adjuvant therapy has also been analysed Experimental data suggest that p53 affects the apoptotic response to anticancer agents, but this has not yet been proven in a clinical series where this demonstration and its effect on therapy could represent one of the most important endpoints in p53 clinical research The use of standardized techniques to evaluate p53 gene mutation and protein accumulation within controlled clinical series of patients entering prospective trials is essential to answer the many remaining questions on the clinical significance of p53 aberrations

The clinical significance of p53 aberrations in human tumours.

We have studied 118 renal cell carcinomas to analyse the expressions of cyclins A and D1 and p21(waf1/cip1), and their relationship to clinical and histopathological parameters as well as to clinical outcome. Cyclins A and D1 and cyclin-dependent kinase inhibitor p21(waf1/cip1) were not expressed in normal renal tissue. Staining signals of cyclin D1 and p21(waf1/cip1) were always nuclear but cyclin A was also expressed in the cytoplasm of the tumour cells. The mean (range) fractions of cyclin A, cyclin D1 and p21(waf1/cip1)-positive tumour cells were 2.2% (range 0–20%), 23.3% (range 0–90%) and 6.8% (range 0–70%) respectively. The expression of cyclin A was related to venous invasion, high nuclear grade, high mitotic rate, high Ki-67 and high PCNA expressions (P ≤ 0.006 for all). The expression of cyclin D1 was linked with age over 65 years, low nuclear grade and high p53 expression (P ≤ 0.05 for all). An inverse correlation was present between p21(waf1/cip1) and cyclin D1 (P = 0.011). Cyclin A predicted survival in the entire study group (P = 0.0014), in T1–4/N0–2/M0 (P = 0.0007) and in T1–2/N0/M0 tumours (P = 0.0007). Cyclin A was also a powerful predictor of disease-free survival in T1–4/N0/M0 (P = 0.0027) tumours (P = 0.0007). Cyclin D1 and p21(waf1/cip1) were not significantly related to survival or disease-free survival in any of the groups. In the entire material the independent prognostic factors were the presence of distant metastases (relative risk (RR) 5.16, P < 0.001), T category (RR 2.68, P < 0.001), Ki-67 expression (RR 1.02, P = 0.026) and cyclin A expression (RR 1.12, P = 0.001). The independent predictors in T1–4/N0/M0 tumours were T-category (RR 2.67, P = 0.001) and cyclin A (RR 1.21, P < 0.001), and in T1–2/N0/M0 tumours the only significant predictor was cyclin A (RR 1.19, P = 0.0002). In renal cell carcinoma, cyclin A is a powerful and independent prognostic factor in all clinical stages of the disease, whereas cyclin D1 and p21(waf1/cip1) have no prognostic value. © 1999 Cancer Research Campaign

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Expression of cyclins A and D and p21(waf1/cip1) proteins in renal cell cancer and their relation to clinicopathological variables and patient survival.

Expressions of proliferating cell nuclear antigen (PC 10), p53 protein (CMI) and c-erbB-2 (NCL-I) were immunohistochemically analysed in 123 renal adenocarcinomas with known follow-up data. e-erbB-2 protein was weakly and focally expressed in 10% of the tumours, and the expression was not related to clinical or histological variables or survival. p53 protein was expressed in 33% of the tumours. Expression of p53 protein was independent of stage, grade and prognosis, while expressions of c-erbB-2 and p53 were weakly interrelated. Proliferating cell nuclear antigen was expressed in all tumours, and the fraction of PC 10-positive nuclei was significantly related to grade, stage and prognosis. Multivariate analysis of clinical, histological and immunohistochemical prognostic factors indicated that the extent of the tumour, its histological differentiation and proliferation rate of the cancer cells are the most important prognostic factors. Recurrence-free survival was related to the fraction of PCIO-positive nuclei, histological differentiation, sex and expression of p53 protein. Over-expression of p53 protein was related to a long recurrence-free survival. Our results show that PC10 immunolabelling can be used to determine the prognostic category in renal adenocarcinoma, whereas the expressions of p53 protein or c-erbB-2 are only weak prognostic indicators. © 1994 Wiley-Liss, Inc.

Expression of proliferating cell nuclear antigen (PC10), p53 protein and c-erbB-2 in renal adenocarcinoma.

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Expression of proliferating cell nuclear antigen (PC10), p53 protein and c-erbB-2 in renal adenocarcinoma.