肝炎和肝细胞癌患者HBV DNA整合的分子特征

StephenW

Cancer. 2018 Sep 7;9(18):3225-3235. doi: 10.7150/jca.26052. eCollection 2018.
Molecular Characterization of HBV DNA Integration in Patients with Hepatitis and Hepatocellular Carcinoma.
Yang L1, Ye S2, Zhao X3, Ji L4, Zhang Y4, Zhou P5, Sun J5, Guan Y4, Han Y6,4, Ni C1, Hu X1, Liu W7, Wang H7, Zhou B8, Huang J6,8,7.
Author information

1
    Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province and Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical Colleg, Shang Tang Road 158, Hangzhou 310014, Zhejiang, P. R China.
2
    Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Qing Chun Road 79, Hangzhou 310003, Zhejiang, P. R. China.
3
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, P. R. China.
4
    Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China.
5
    STD Institute, Shanghai Skin Disease Hospital, Tong Ji University, Shanghai, China.
6
    Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Chinese National Human Genome Center at Shanghai. Shanghai Jiao Tong University, Shanghai, 200240, China.
7
    Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, 518112, China.
8
    Shenzhen People's Hospital, Second Clinical Medical College of Jinan University. Shenzhen, 518109, China.

Abstract

Infection by chronic hepatitis B virus (HBV) is one of the major causes of liver cirrhosis and primary hepatocellular carcinoma (HCC). Viral DNA integration into the host cell genome is a key mechanism of hepatocarcinogenesis. However, the molecular characterization and the potential clinical implications of HBV DNA integration into patients suffering from different hepatitis and HCC remain unclear. In this study, we analyzed HBV integrations in patients with hepatitis B and HCC using HBV probe-based capturing and next-generation sequencing. The results revealed that the sizes of the HBV integrations ranged from 28 bp to 3215 bp, including the full-length HBV DNA sequence. The integration breakpoints were preferentially distributed in the viral enhancer, X protein, and core protein regions of the HBV genome. The number of HBV integrations followed an increasing trend from hepatitis to HCC, which was positively correlated with the HBV virus load in patients with hepatitis. The number of HBV integrations in the HBeAg positive chronic hepatitis B group was significantly greater than that in the other hepatitis B groups (P < 0.05). However, the relative abundance of HBV integrations was significantly higher in HCC tissues than in the adjacent liver tissues. Interestingly, 61.6% (8/13) of HBV-human DNA integration fragments could be detected at the RNA level. Our results also showed that HBV integration-targeted genes (ITGs) were significantly enriched in many cancer-related pathways, such as MAPK, extracellular matrix (ECM)-receptor interaction, and the hedgehog signaling pathway. Individuals with HBV integrations exhibited shorter disease-free survival (DFS) and overall survival (OS) than those without HBV integrations in some ITGs including LINC00293 (long intergenic non-protein coding RNA 293; DFS P = 0.008, OS P = 0.009), FSHB (follicle stimulating hormone beta subunit; DFS P = 0.05, OS P = 0.186), and LPHN3 (latrophilin-3; DFS P = 0.493, OS P = 0.033). This study determined the underlying mechanism of HBV DNA integration in liver diseases and laid the foundation for future studies on the pathogenesis of liver cancer.
KEYWORDS:

Capture sequencing; Chronic hepatitis B virus; HBV integration.; Hepatocellular carcinoma

PMID:
    30271481
PMCID:
    PMC6160693
DOI:
    10.7150/jca.26052

StephenW

癌症。 2018年9月7日; 9（18）：3225-3235。 doi：10.7150 / jca.26052。 eCollection 2018。
肝炎和肝细胞癌患者HBV DNA整合的分子特征。
Yang L1，Ye S2，Zhao X3，Ji L4，Zhang Y4，Zhou P5，Sun J5，Guan Y4，Han Y6,4，Ni C1，Hu X1，Liu W7，Wang H7，Zhou B8，Huang J6,8,7 。
作者信息

1
    浙江省肿瘤分子诊断与个体医学重点实验室，浙江省消化内科重点实验室，浙江省人民医院，杭州医学院人民医院，上唐路158号，浙江杭州310014，中国。
2
    浙江大学医学院附属第一医院外科，肝胆胰外科，浙江杭州310003青春路79号，中国。
3
    浙江大学医学院附属第一医院传染病诊断与治疗国家重点实验室，传染病诊疗协同创新中心，浙江杭州310003，中国。
4
    中国天津滨海基因组研究所，天津，300308
五
    上海同济大学上海市皮肤病医院性病研究所，上海
6
    系统生物医学教育部重点实验室和系统生物医学协同创新中心，上海中国人类基因组中心系统生物医学中心。上海交通大学，上海，200240
7
    广东医学院深圳市第三人民医院感染与免疫深圳市重点实验室，深圳518112
8
    暨南大学第二临床医学院深圳市人民医院。深圳，518109，中国。

抽象

慢性乙型肝炎病毒（HBV）感染是肝硬化和原发性肝细胞癌（HCC）的主要原因之一。病毒DNA整合到宿主细胞基因组中是肝癌发生的关键机制。然而，HBV DNA整合到患有不同肝炎和HCC的患者中的分子特征和潜在的临床意义仍不清楚。在这项研究中，我们使用基于HBV探针的捕获和下一代测序分析了乙型肝炎和HCC患者的HBV整合。结果显示，HBV整合的大小范围为28bp至3215bp，包括全长HBV DNA序列。整合断点优先分布在HBV基因组的病毒增强子，X蛋白和核心蛋白区域中。 HBV整合的数量随着从肝炎到HCC的增加趋势而增加，这与肝炎患者的HBV病毒载量呈正相关。 HBeAg阳性慢性乙型肝炎组HBV整合数明显高于其他乙型肝炎组（P <0.05）。然而，HCC组织中HBV整合的相对丰度显着高于邻近肝组织。有趣的是，可以在RNA水平检测到61.6％（8/13）的HBV-人DNA整合片段。我们的研究结果还表明，HBV整合靶向基因（ITGs）在许多癌症相关途径中显着富集，如MAPK，细胞外基质（ECM） - 受体相互作用和hedgehog信号通路。 HBV整合个体的无病生存期（DFS）和总生存期（OS）显着低于某些ITG中无HBV整合的个体，包括LINC00293（长基因间非蛋白编码RNA 293; DFS P = 0.008，OS P = 0.009）， FSHB（卵泡刺激素β亚基; DFS P = 0.05，OS P = 0.186）和LPHN3（latrophilin-3; DFS P = 0.493，OS P = 0.033）。本研究确定了HBV DNA整合在肝脏疾病中的潜在机制，为今后研究肝癌的发病机制奠定了基础。
关键词：

捕获测序;慢性乙型肝炎病毒; HBV整合。肝细胞癌

结论：
    30271481
PMCID：
    PMC6160693
DOI：
    10.7150 / jca.26052