结节状结节的肝细胞癌多区域全基因组测序揭示了癌症的逐

StephenW

Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution
Haruhiko Takeda  1 , Atsushi Takai  1 , Ken Kumagai  1 , Eriko Iguchi  1 , Soichi Arasawa  1 , Yuji Eso  1 , Takahiro Shimizu  1 , Yoshihide Ueda  1 , Kojiro Taura  2 , Shinji Uemoto  2 , Ryuichi Kita  3 , Hironori Haga  4 , Hiroyuki Marusawa  1   3 , Akihiro Fujimoto  5 , Hiroshi Seno  1
Affiliations
Affiliations

    1
    Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan.
    2
    Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
    3
    Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.
    4
    Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
    5
    Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

    PMID: 32815153 DOI: 10.1002/path.5533

Abstract

Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy-number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well-differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and intertumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. This article is protected by copyright. All rights reserved.

Keywords: TERT; cancer evolution; early hepatocellular carcinoma; genetic landscape; hepatocarcinogenesis; heterogeneity; structural variation.

This article is protected by copyright. All rights reserved.

StephenW

结节状结节的肝细胞癌多区域全基因组测序揭示了癌症的逐步发展
武田春彦1，笃田敦1，熊谷贤1，井口惠里子1，新泽晃一1，宇治英世1，清水孝宏1，植田义秀1，小次郎太郎2，上本真司2，龙田北一3，广田博多4，丸泽弘之1 3，藤本昭弘5，仙野弘1
隶属关系
隶属关系

    1个
    胃肠病学和肝病学系；日本京都大学大学院医学研究科。
    2
    日本京都大学医学研究生院肝胆胰胰腺和移植手术科。
    3
    日本大阪红十字会医院消化内科和肝病科。
    4
    日本京都大学医院诊断病理科。
    5
    日本京都大学医学院研究生院药物发现医学系。

    PMID：32815153 DOI：10.1002 / path.5533

抽象

最近的遗传学分析显示了肝细胞癌（HCC）的遗传异质性，尽管目前尚不清楚遗传改变如何导致HCC的多阶段进展，尤其是从血管下肝结节到高血管HCC的早期阶段。我们对具有结节状结节的HCC进行了多区域全基因组测序，该结节由内部高血管HCC和起源于共同起源的低血管HCC包围着，并鉴定了每个样本中的点突变，结构变异和拷贝数变异。根据内部和外部区域的遗传景观，以及病理和放射学发现，我们研究了癌细胞从缓慢生长的HCC到快速生长的HCC的逐步进化。我们首先证明，由血管高度分化的HCC组成的大多数肿瘤细胞已经具有数千个点突变，甚至具有几个结构变异，包括染色体易位和染色质增生，这是干细胞事件。端粒酶逆转录酶（TERT）相关的畸变，包括启动子突变，染色体易位和乙型肝炎病毒DNA整合以及异常的甲基化状态，通常被检测为躯干畸变，而与肝癌相关的各种基因在每种情况下，在内部已分化的结节中均已积累。此外，在每种情况下，主干和分支突变特征的差异都表明了诱变的多步骤贡献。总之，与TERT基因相关的基因组改变可能是形成血管HCC的关键驱动因素，在发展阶段还会积累更多病例特异性驱动基因突变，从而形成肿瘤内和肿瘤间异质性，从而证实了靶向检测之前基因检测的重要性治疗。这些数据阐明了多步肝癌发生的过程，将有助于研究HCC的新治疗策略。本文受版权保护。版权所有。

关键词：TERT；癌症演变；早期肝细胞癌；基因景观肝癌发生异质性结构变异。

本文受版权保护。版权所有。