Large-scale analysis of the genetic and epigenetic alterations in hepatocellular carcinoma from Southeast China
Large-scale analysis of the genetic and epigenetic alterations in hepatocellular carcinoma from Southeast China
复制标题
中国东南部肝细胞癌遗传和表观遗传改变的大规模分析
DOI：
10.1016/j.mrfmmm.2008.02.005
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发表时间：
2008-05-10
影响因子：
2.3
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
--
作者：
Su, Hang;Zhao, Jing;Zhuang, Shi-Mei
由于缺乏对同一组肝细胞癌（HCC）进行全面的遗传学和表观遗传学分析，我们对肝癌发生过程中分子改变的认识仍然是零碎的。在这项研究中，我们进行了大规模的分析，包括50个基因的突变筛查和54对HCC及其邻近非癌组织中3个基因的甲基化检测。所有样本均采集自中国东南部的居民。我们发现HBV感染和慢性肝炎/肝硬化的病例分别为83.3%和98.1%。在54个样本中的18个（33.3%）中鉴定出突变，其中14个病例中有p53改变，4个肿瘤中有β-连环蛋白突变。在邻近组织中未发现突变。有趣的是，14例携带p53突变的肿瘤中有9例（64.3%）在密码子249处显示丝氨酸被精氨酸取代，这是一种被认为是由黄曲霉毒素B1诱导的特征性变化。此外，p53突变与较短的无复发生存期显著相关（P = 0.004）。结果还显示，在高达90%的肿瘤和40%的邻近组织中，两个或多个基因存在异常甲基化。RASSF 1A基因甲基化在肝癌及癌旁组织中的发生率明显高于p16 INK 4a和HAI 2基因，提示RASSF 1A基因的异常可能先于其他两个基因。这些数据表明，异常甲基化发生在突变之前，是这组HCC发展的早期事件。我们的研究结果强调了p53作为HCC的预后因素，RASSF 1A作为预防肝细胞恶性转化的潜在靶点。(C)2008 Elsevier B. V.保留所有权利。
Our knowledge about molecular alterations during hepatocarcinogenesis is still fragmentary, due to lack of comprehensive genetic and epigenetic analyses in the same set of hepatocellular carcinomas (HCCs). In this study, we conducted a large-scale analysis, including mutation screening in 50 genes and methylation assays in three genes in 54 pairs of HCCs and their neighboring non-cancerous tissues. All samples were collected from the residents in Southeast China. We found HBV infection and chronic hepatitis/cirrhosis in 83.3% and 98.1% of the cases, respectively. Mutations were identified in 18 out of 54 (33.3%) samples, with p53 alterations in 14 cases and beta-catenin mutations in four tumors. No mutations were identified in the neighboring tissues. Interestingly, 9 out of 14 (64.3%) tumors carrying p53 mutations displayed substitution of serine by arginine at codon 249, a characteristic change believed to be induced by aflatoxin-B1. Furthermore, p53 mutation was significantly associated with shorter recurrence-free survival (P = 0.004). The results also revealed aberrant methylation in two or more genes in as high as 90% of tumors and 40% of adjacent tissues. The frequency of RASSF1A hypermethylation was much higher than that of p16INK4a and HAI2 in both HCC and neighboring tissues, indicating that deregulation of RASSF1A may precede the other two genes. These data suggest that aberrant methylation occurs before mutation and is an early event in the development of this set of HCC. Our findings highlight p53 as a prognostic factor of HCC and RASSF1A as a potential target in preventing malignant transformation of hepatocytes. (C) 2008 Elsevier B.V. All rights reserved.