Correlation of TP53 mutations with HCV positivity in hepatocarcinogenesis: Identification of a novel TP53 microindel in hepatocellular carcinoma with HCV infection
Correlation of TP53 mutations with HCV positivity in hepatocarcinogenesis: Identification of a novel TP53 microindel in hepatocellular carcinoma with HCV infection
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肝癌发生中 TP53 突变与 HCV 阳性的相关性：HCV 感染肝细胞癌中新型 TP53 微插入的鉴定
DOI：
10.3892/or.2013.2430
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发表时间：
2013-07-01
期刊：
影响因子：
4.2
通讯作者：
Huang, Jian
中科院分区：
文献类型：
--
作者：
Long, Jiang;Wang, Yan;Huang, Jian
虽然已知慢性丙型肝炎病毒（HCV）感染可能有助于肿瘤的发生和发展，但导致肝细胞癌（HCC）的分子过程仍不清楚。微缺失是一种独特的、罕见的突变，它会导致在同一核苷酸位置插入和删除序列，是癌症的重要诱因。迄今为止，肿瘤抑制基因p53 （TP53）中的微指数尚未在肿瘤中得到充分研究。在本研究中，通过单链构象多态性分析和直接测序，筛选116例HCC患者TP53基因（外显子5-8）突变。一种特殊类型的复杂TP53突变，616ins14del1(14-1微indel)，在HCC合并HCV感染的病例中被发现。这种罕见的TP53微缺失导致产生211个氨基酸的截断蛋白，缺乏dna结合结构域和四聚化结构域。免疫组化显示肿瘤细胞中p53蛋白表达缺失，p21（WAF/CIP）、Mdm2、Bax下调，提示p53信号通路受损。116例hcc中有19例（16.4%）共携带19个TP53突变。值得注意的是，13例HCV阳性病例中有5例（38.5%）含有TP53突变，TP53突变与HCV阳性之间存在显著相关性（P=0.0379）。TP53突变与乙型肝炎病毒（HBV）阳性无相关性。总之，我们在HCC中发现了一个新的TP53微靶，并提供了HCC以HCV感染为特征的证据，这些HCC通常与TP53基因的突变失活相关。
Although it is known that chronic hepatitis C virus (HCV) infection may contribute to tumor initiation and development, the molecular processes causing hepatocellular carcinoma (HCC) remain unclear. Microindels are unique, infrequent mutations that result in inserted and deleted sequences at the same nucleotide position, and are important contributors to cancer. To date, microindels in the p53 tumor suppressor gene (TP53) have not been fully examined in tumors. In the present study, 116 cases of HCC were screened for mutations in the TP53 gene (exon 5-8) by single-stranded conformational polymorphism analysis followed by direct sequencing. A special type of complex TP53 mutation, 616ins14del1 (14-1 microindel), was identified in a case of HCC with HCV infection. This rare TP53 microindel led to the generation of a truncated protein of 211 amino acids that lacked the DNA-binding domain and tetramerization domain. Immunohistochemistry showed loss of p53 protein expression and downregulation of p21(WAF/CIP), Mdm2 and Bax in the tumor cells, indicating an impaired p53 signaling pathway. Nineteen of the 116 (16.4%) HCCs carried a total of 19 TP53 mutations. Notably, 5 of the 13 HCV-positive (38.5%) cases contained a TP53 mutation, and there was a significant association between TP53 mutations and HCV positivity (P=0.0379). No correlation of TP53 mutations with hepatitis B virus (HBV) positivity was observed. In summary, we identified a novel TP53 microindel in HCC, and provided evidence of HCC characterized by HCV infections typically associated with mutational inactivation of the TP53 gene.