通过单细胞基因组测序揭示了HBV相关肝细胞癌中克隆进化的

StephenW

Diverse modes of clonal evolution in HBV-related hepatocellular carcinoma revealed by single-cell genome sequencing

    Meng Duan, Junfeng Hao, Sijia Cui, Daniel L Worthley, Shu Zhang, Zhichao Wang, Jieyi Shi, Longzi Liu, Xiaoying Wang, Aiwu Ke, Ya Cao, Ruibin Xi, Xiaoming Zhang, Jian Zhou, Jia Fan, Chong Li & Qiang Gao

    Cell Research volume 28, pages 359–373 (2018)
    doi:10.1038/cr.2018.11
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Received:
    01 April 2017
Revised:
    13 July 2017
Accepted:
    12 December 2017
Published online:
    12 January 2018

Abstract

Hepatocellular carcinoma (HCC) is a cancer of substantial morphologic, genetic and phenotypic diversity. Yet we do not understand the relationship between intratumor heterogeneity and the associated morphologic/histological characteristics of the tumor. Using single-cell whole-genome sequencing to profile 96 tumor cells (30-36 each) and 15 normal liver cells (5 each), collected from three male patients with HBV-associated HCC, we confirmed that copy number variations occur early in hepatocarcinogenesis but thereafter remain relatively stable throughout tumor progression. Importantly, we showed that specific HCCs can be of monoclonal or polyclonal origins. Tumors with confluent multinodular morphology are the typical polyclonal tumors and display the highest intratumor heterogeneity. In addition to mutational and copy number profiles, we dissected the clonal origins of HCC using HBV-derived foreign genomic markers. In monoclonal HCC, all the tumor single cells exhibit the same HBV integrations, indicating that HBV integration is an early driver event and remains extremely stable during tumor progression. In addition, our results indicated that both models of metastasis, late dissemination and early seeding, have a role in HCC progression. Notably, early intrahepatic spreading of the initiating clone leads to the formation of synchronous multifocal tumors. Meanwhile, we identified a potential driver gene ZNF717 in HCC, which exhibits a high frequency of mutation at both single-cell and population levels, as a tumor suppressor acting through regulating the IL-6/STAT3 pathway. These findings highlight multiple distinct tumor evolutionary mechanisms in HCC, which suggests the need for specific treatment strategies.

StephenW

通过单细胞基因组测序揭示了HBV相关肝细胞癌中克隆进化的多种模式

    孟端郝俊峰崔斯佳Daniel L Worthley张书王志超施杰义刘龙子王晓英王爱英柯爱武曹雅张瑞斌张小明周建贾帆钟立强高

    Cell Research第28卷，第359-373页（2018）
    DOI：10.1038 / cr.2018.11
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收稿日期：
    2017年4月1日
修订：
    2017年7月13日
公认：
    2017年12月12日
在线发布：
    2018年1月12日

抽象

肝细胞癌（HCC）是一种具有重要形态，遗传和表型多样性的癌症。然而，我们不了解肿瘤异质性与肿瘤相关的形态/组织学特征之间的关系。我们使用单细胞全基因组测序来分析从三名具有HBV相关HCC的男性患者收集的96个肿瘤细胞（每个30-36个）和15个正常肝细胞（每个5个），我们证实了在肝癌发生早期出现拷贝数变异但此后在肿瘤进展过程中保持相对稳定。重要的是，我们表明具体的HCC可以是单克隆或多克隆起源。具有融合多结节形态的肿瘤是典型的多克隆肿瘤并显示出最高的肿瘤内异质性。除了突变和拷贝数概况外，我们还使用HBV衍生的外源基因组标记解剖了HCC的克隆起源。在单克隆HCC中，所有肿瘤单个细胞表现出相同的HBV整合，表明HBV整合是早期的驱动事件并且在肿瘤进展期间保持非常稳定。此外，我们的研究结果表明，转移，晚期播散和早期播种两种模型均在HCC进展中起作用。值得注意的是，初始克隆的早期肝内扩散导致同步多灶性肿瘤的形成。同时，我们发现HCC中潜在的驱动基因ZNF717，其在单细胞和群体水平都表现出高频率的突变，作为通过调节IL-6 / STAT3途径起作用的肿瘤抑制剂。这些发现强调了HCC中多种不同的肿瘤进化机制，这表明需要特定的治疗策略。