Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis
Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis
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DOI：
10.1007/s00535-019-01555-z
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发表时间：
2019-07-01
影响因子：
6.3
通讯作者：
Marusawa, Hiroyuki
中科院分区：
文献类型：
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作者：
Kim, Soo Ki;Takeda, Haruhiko;Marusawa, Hiroyuki
研究背景肝细胞癌在含有大量再生结节(RN)的肝硬变中反复发展。然而，RNS的生物学致瘤潜力仍然不清楚。为了揭示肝硬变肿瘤发生的分子基础，我们利用下一代测序技术研究了肝硬变组织中RN的遗传异常。方法随机选择10例活体供肝移植患者的全肝组织，分离205个RN和7个肝癌组织。对筛选出的30个肝癌相关基因进行全外显子测序和额外的靶向深度测序，揭示RN和HC的突变格局。结果外显子全测序显示RN经常具有相对较高丰度的遗传改变，提示每个RN在肝硬变中都具有克隆性结构。在RNS中观察到的突变特征与在肝细胞癌中发现的相似，其特征是以C>；T转变为主，其次是T>；C和C>；A突变。RN的定向深度测序分析发现了各种肿瘤相关基因的非同义低丰度突变，包括TP53和ARID1A。相反，在任何被检查的RN中都没有检测到TERT启动子突变。RN中TERT的表达水平与正常肝组织相当，而所有肝细胞癌组织中TERT的表达水平均高于正常肝组织。结论对RN构建肝硬变的分析表明，在临床和组织学显性肝细胞癌发生之前，多种基因异常在肝硬变肝脏中积累。RN的这些异常可能为肝硬变患者的肿瘤发生提供了基础。
BackgroundHepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing.MethodsWe isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs.ResultsWhole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including TP53 and ARID1A. In contrast, TERT promoter mutations were not detected in any of the RNs examined. Consistently, TERT expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of TERT expression.ConclusionAnalyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.