Semczuk Andrzej, Marzec Barbara, Skomra Danuta, Roessner Albert, Cybulski Marek, Rechberger Tomasz, Schneider-Stock Regine
Second Department of Gynecology, Lublin University School of Medicine, Lublin, Poland.
Oncology. 2005;69(4):317-25. doi: 10.1159/000089764. Epub 2005 Nov 17.
We examined loss of heterozygosity (LOH) at the TP53 gene in primary human endometrial carcinomas (EC), and investigated the relationship between allelic loss, p53 protein overexpression, pRb-1 pathway alterations and MIB-1 proliferative activity. Applying the non-isotopic PCR-RFLP/VNTR-silver staining techniques, we investigated TP53 LOH in 46 tumors at four polymorphic loci. Out of 42 informative carcinomas, LOH was found in 19% of the cases studied. In general, there was no significant relationship between LOH and the clinical and pathological variables of cancer, including patient age, clinical stage, histological grade or depth of myometrial invasion. Interestingly, none of 7 tumors associated with hyperplasia revealed allelic imbalance, whereas 8 of 27 (30%) tumors without hyperplasia exhibited LOH (p=0.312; Fisher's exact test). Overexpression of nuclear p53 was not correlated with allelic loss at TP53 (p=0.336, Fisher's exact test). It is worth pointing out that p53 immunoreactivity was significantly related to proliferative activity of cancer (R=0.42, p=0.0037; Spearman's rank correlation test). A tendency towards a poorer outcome was reported in EC patients displaying TP53 LOH during short-time follow-up (p=0.093; log-rank test). None of the tumors simultaneously showed LOH at TP53 and RB1 genes (R=-0.211, p=0.16; Spearman's rank correlation test). p16INK4A alterations (LOH and gene deletion) occurred concomitantly, with 3 tumors showing the TP53 allelic loss, whereas the cyclin D1/cdk4 complex was overexpressed in a case with TP53 LOH. Altogether, losses at TP53 were not associated with p53 nuclear overexpression, but may affect a subset of EC patients characterized by an unfavorable prognosis at short-time follow-up. Allelic loss at TP53 seems to arise independently of LOH at the RB1 gene in carcinomas of the uterine corpus in humans. Disruptions at p16INK4A and/or cdk4/cyclin D1 concomitantly occurring with TP53 LOH may participate in the development of a subset of endometrioid-type ECs.
我们检测了原发性人类子宫内膜癌（EC）中TP53基因的杂合性缺失（LOH），并研究了等位基因缺失、p53蛋白过表达、pRb - 1通路改变与MIB - 1增殖活性之间的关系。应用非同位素PCR - RFLP/VNTR - 银染技术，我们在46个肿瘤的4个多态性位点检测了TP53 LOH。在42个信息丰富的癌组织中，19%的研究病例发现有LOH。一般来说，LOH与癌症的临床和病理变量之间无显著关系，这些变量包括患者年龄、临床分期、组织学分级或肌层浸润深度。有趣的是，7个与增生相关的肿瘤均未显示等位基因失衡，而27个（30%）无增生的肿瘤中有8个表现出LOH（p = 0.312；Fisher精确检验）。核p53的过表达与TP53处的等位基因缺失无关（p = 0.336，Fisher精确检验）。值得指出的是，p53免疫反应性与癌症的增殖活性显著相关（R = 0.42，p = 0.0037；Spearman等级相关检验）。在短期随访中，显示TP53 LOH的EC患者报告有预后较差的倾向（p = 0.093；对数秩检验）。没有肿瘤同时显示TP53和RB1基因的LOH（R = -0.211，p = 0.16；Spearman等级相关检验）。p16INK4A改变（LOH和基因缺失）同时发生，3个肿瘤显示TP53等位基因缺失，而在1例有TP53 LOH的病例中细胞周期蛋白D1/cdk4复合物过表达。总之，TP53缺失与p53核过表达无关，但可能影响一部分在短期随访中预后不良的EC患者。在人类子宫体癌中，TP53的等位基因缺失似乎独立于RB1基因的LOH而出现。与TP53 LOH同时发生的p16INK4A和/或cdk4/细胞周期蛋白D1的破坏可能参与了一部分子宫内膜样型EC的发生发展。
