HBeAg血清学转换过程中乙型肝炎病毒DNA整合的序列分析

StephenW

Emerg Microbes Infect. 2018 Aug 8;7(1):142. doi: 10.1038/s41426-018-0145-7.
Sequence analysis of integrated hepatitis B virus DNA during HBeAg-seroconversion.
Budzinska MA1, Shackel NA1,2,3, Urban S4,5, Tu T6.
Author information

1
    Centenary Institute, University of Sydney, Sydney, 2050, NSW, Australia.
2
    South Western Sydney Clinical School, University of New South Wales, Sydney, 2170, NSW, Australia.
3
    Liverpool Hospital, Gastroenterology, Sydney, 2170, NSW, Australia.
4
    Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, D-69120, Germany.
5
    German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, D-69120, Germany.
6
    Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, D-69120, Germany. [email protected].

Abstract

Hepatitis B virus (HBV) integration into the host cell genome occurs early on in infection and reportedly induces pro-oncogenic changes in hepatocytes that drive HCC initiation. However, it remains unclear when these changes occur during hepatocarcinogenesis. Extensive expansion of hepatocyte clones with a selective advantage was shown to occur prior to cancer formation during the HBeAg-seroconversion phase of chronic HBV infection. We hypothesized that since integrations occur during the early stages of infection, cell phenotype could be altered and induce a selection advantage (e.g., through insertional mutagenesis or cis-mediated activation of downstream genes). Here, we analyzed the enrichment of genomic and functional patterns in the cellular host sequence adjacent to HBV DNA integration events. We examined 717 unique integration events detected in patients who have and have not undergone HBeAg-seroconversion (n = 41) or in an in vitro model system. We also used an in silico model to control for detection biases. We showed that the sites of HBV DNA integration were distributed throughout the entire host genome without obvious enrichment of specific structural or functional genomic features in the adjacent cellular genome during HBeAg-seroconversion. Currently, this is the most comprehensive characterization of HBV DNA integration events prior to hepatocarcinogenesis. Our results suggest no significant selection for (or against) specific cellular sites of HBV DNA integration occur during the clonal expansion phase of chronic HBV infection. Thus, HBV DNA integration events likely represent passenger events rather than active drivers of liver cancer, which was previously suggested.

PMID:
    30087321
DOI:
    10.1038/s41426-018-0145-7

StephenW

Emerg Microbes Infect。 2018年8月8日; 7（1）：142。 doi：10.1038 / s41426-018-0145-7。
HBeAg血清学转换过程中乙型肝炎病毒DNA整合的序列分析。
Budzinska MA1，Shackel NA1,2,3，Urban S4,5，Tu T6。
作者信息

1
    悉尼悉尼大学百年研究所，2050年，澳大利亚新南威尔士州。
2
    悉尼南悉尼大学临床医学院，悉尼新南威尔士州2170，澳大利亚新南威尔士州。
3
    利物浦医院，消化内科，悉尼，2170，新南威尔士州，澳大利亚。
4
    海德堡大学医院分子病毒学传染病系，德国D-69120，D-69120。
五
    德国感染研究中心（DZIF），合作伙伴Site Heidelberg，Heidelberg，D-69120，德国。
6
    海德堡大学医院分子病毒学传染病系，德国D-69120，D-69120。 [email protected]。

抽象

乙型肝炎病毒（HBV）整合到宿主细胞基因组中发生在感染的早期，并且据报道诱导肝细胞中的致癌基因变化驱动HCC起始。然而，在肝癌发生过程中何时发生这些变化尚不清楚。具有选择性优势的肝细胞克隆的广泛扩增显示在慢性HBV感染的HBeAg-血清转化期期间癌症形成之前发生。我们假设由于整合发生在感染的早期阶段，细胞表型可以被改变并诱导选择优势（例如，通过插入诱变或顺式介导的下游基因激活）。在这里，我们分析了与HBV DNA整合事件相邻的细胞宿主序列中基因组和功能模式的富集。我们检查了在已经和未经历HBeAg血清转换（n = 41）的患者中或在体外模型系统中检测到的717个独特整合事件。我们还使用计算机模型来控制检测偏差。我们发现HBV DNA整合的位点分布在整个宿主基因组中，而在HBeAg血清转换期间没有明显富集相邻细胞基因组中的特定结构或功能基因组特征。目前，这是肝癌发生前HBV DNA整合事件的最全面的表征。我们的结果表明，在慢性HBV感染的克隆扩增阶段期间，没有显着选择（或反对）HBV DNA整合的特定细胞位点。因此，HBV DNA整合事件可能代表乘客事件，而不是之前建议的肝癌的主动驱动因素。

结论：
    30087321
DOI：
    10.1038 / s41426-018-0145-7