ALTERED PATTERNS OF MDM2 AND TP53 EXPRESSION IN HUMAN BLADDER-CANCER
ALTERED PATTERNS OF MDM2 AND TP53 EXPRESSION IN HUMAN BLADDER-CANCER
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DOI：
10.1093/jnci/86.17.1325
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发表时间：
1994-09-07
期刊：
影响因子：
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通讯作者：
CORDONCARDO, C
中科院分区：
文献类型：
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作者：
LIANES, P;ORLOW, I;CORDONCARDO, C
背景资料：TP 53基因定位于17号染色体短臂（17p13.1），编码一个53 kd的核磷蛋白（p53），参与细胞周期控制。MDM 2基因位于12号染色体长臂（12 q13 -14），编码一个分子量为90 kd的核蛋白（Mdm 2）。据报道，TP 53基因的遗传改变是膀胱癌的常见事件，并与疾病进展相关。MDM 2基因已被证明是扩增和过度表达的肉瘤，然而，这些变化尚未被分析在肿瘤性病变的膀胱，目的：我们进行了本研究，以确定频率的MDM 2和TP 53异常的膀胱肿瘤，以及检查的临床相关性，确定其改变模式的表达与膀胱癌患者。方法：我们分析了87例膀胱肿瘤患者的队列。Mdm 2蛋白表达的改变模式用单克隆抗体2A 10的免疫组化测定来确定，并且MDM 2基因扩增仅通过Southern印迹来研究。使用单克隆抗体PAb 1801鉴定突变型p53蛋白。利用单链构象多态性评估TP 53基因中基因内突变的存在，并通过测序进一步表征。通过双尾Fisher精确检验对相关性进行统计学评估。结果：87例中有26例Mdm 2蛋白异常高水平，但只有1例显示Mdm 2扩增。87例中有36例p53蛋白核过度表达。16例患者同时存在Mdm 2和p53蛋白的异常高表达。Mdm 2和p53过表达之间有很强的统计学相关性（Fisher精确检验：P = 0.018）。此外，Mdm 2过表达与低分期、低级别膀胱肿瘤之间存在显著相关性（Fisher精确检验：P = .0005）。结论：结果表明，异常的Mdm 2和p53表型是膀胱癌的常见事件，并且可能参与尿路上皮肿瘤的发生或肿瘤进展。含义：这项研究是第一个报告改变模式的MDM 2表达在人类膀胱肿瘤，并表明，异常的MDM 2和p53表型可能是重要的诊断和预后标志物受膀胱癌的患者。
Background: The TP53 gene maps to the short arm of chromosome 17 (17p13.1) 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 chromosome 12 (12q13-14), and it encodes for a nuclear protein (Mdm2) of 90 kd of molecular mass. Genetic alterations in the TP53 gene have been reported as frequent events in bladder cancer and are associated with disease progression. The MDM2 gene has been shown to be amplified and overexpressed in sarcomas; however, these changes have not yet been analyzed in neoplastic lesions of the urinary bladder, Purpose: We undertook the present study in order to determine the frequency of MDM2 and TP53 abnormalities in bladder tumors, as well as to examine the clinical 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 expression of Mdm2 proteins were determined using an immunohistochemical assay with monoclonal antibody 2A10, and MDM2 gene amplifications mere studied by Southern blotting. Mutant p53 proteins were identified using monoclonal antibody PAb1801. The presence of intragenic mutations in the TP53 gene were assessed utilizing single-strand conformation polymorphism and further characterized by sequencing. Associations were assessed statistically by the two-tailed Fisher's exact test. Results: Twenty-six of 87 cases had abnormally high levels of Mdm2 proteins; however, only one case showed an MDM2 amplification. Thirty-six of 87 cases displayed p53 nuclear overexpression. Sixteen cases had abnormally high 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 overexpression and low-stage, low-grade bladder tumors (Fisher's exact test: P = .0005). Conclusions: The results suggest that aberrant Mdm2 and p53 phenotypes are frequent events in bladder cancer and mag be involved in tumorigenesis or tumor progression in urothelial neoplasias. Implications: This study is the first to report altered patterns of MDM2 expression in human bladder tumors and demonstrates that aberrant Mdm2 and p53 phenotypes may be important diagnostic and prognostic markers in patients affected by bladder cancer.