p53/MDM2 Research Group, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.
BJU Int. 2012 Apr;109(8):1250-7. doi: 10.1111/j.1464-410X.2011.10433.x. Epub 2011 Jul 14.
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.
为了解决围绕肾细胞癌（RCC）中 p53 功能、表达和突变的诸多争议问题，我们进行了首次同时测定 p53/MDM2 表达、TP53 突变状态（在 p53 阳性患者中）以及 RCC 患者预后的研究。
总共对 90 例接受根治性肾切除术治疗的 RCC 患者的标本进行了 p53 和 MDM2 的组织微阵列免疫组化分析，并对 p53 阳性样本进行了 p53 的功能和基因分析。通过 Kaplan-Meier 法进行生存分析，并采用单因素分析确定随后进行的多因素分析中与临床参数和生物标志物表达相关的变量。
RCC 中 p53 的上调与 MDM2 的上调密切相关（P<0.001）。p53 和 MDM2 的共表达增加可通过单因素（P=0.036）和 Cox 多因素回归分析（P=0.027；相对风险，3.20）识别出疾病特异性生存率显著降低的患者。对具有增加的 p53 表达的肿瘤进行的功能（即在酵母中分离等位基因的功能分析）和遗传分析表明，大多数患者（86%）保留野生型 p53。
p53/MDM2 的共表达确定了预后不良的患者亚组，尽管他们所有患者都患有局限性疾病。上调的 p53 通常为野生型，因此为 p53 与 MDM2 表达之间的关联提供了一种机制解释：上调的野生型 p53 可能促进了观察到的 MDM2 共表达。本研究的结果表明，p53 途径以组织/疾病特异性的方式发生改变，应该研究针对该途径的治疗策略，以确定是否可以挽救 RCC 中的 p53 肿瘤抑制功能。
