乙型肝炎病毒前基因组RNA在肝细胞癌

StephenW

Hepatitis B Virus Pregenomic RNA in Hepatocellular Carcinoma: A Nosological and Prognostic Determinant

    Boris Halgand1, Christophe Desterke2, Lise Rivière3, Guillaume Fallot2, Mylène Sebagh2, Julien Calderaro4, Paulette Bioulac-Sage5, Christine Neuveut3, Marie-Annick Buendia2, Didier Samuel2 andCyrille Féray4,*

Version of Record online: 19 DEC 2017

DOI: 10.1002/hep.29463

© 2017 by the American Association for the Study of Liver Diseases.


Hepatology

Volume 67, Issue 1, pages 86–96, January 2018
Article has an altmetric score of 1

    1    INSERM U948, Institut des Maladies de l'Appareil Digestif, CHU de Nantes, France
    2    INSERM U1193, Paris-Sud University, Paul Brousse Hospital, Villejuif, France
    3    Unité Hepacivirus et Immunité Innée, CNRS URA 3015, Institut Pasteur, Paris, France
    4    INSERM U955, Paris-Est-Créteil University, Henri Mondor Hospital, Créteil, France
    5    Pathology Department, CHU Bordeaux, INSERM U1053, Bordeaux 2 University, Bordeaux, France

Email: Cyrille Féray ([email protected])

*ADDRESS CORRESPONDENCE AND REPRINT REQUESTS:
Cyrille Féray, M.D., Ph.D.
INSERM-U955, Institut Henri Mondor
51 Avenue du Maréchal de Lattre de Tassigny
94010 Créteil, France
E-mail: [email protected]
Tel: 33(0)149812123

    Potential conflict of interest: Dr. Samuel consults for Astellas, Bristol-Myers Squibb, Gilead, LFB, MSD, Roche, Biotest, AbbVie, and Intercept.

    Supported (PAIRINCA CHC, 2009) by the “Agence Nationale Recherche sur le SIDA” (ANRS), the “Institut National du Cancer” (INCA), the “Association pour la Recherche Contre le Cancer” (ARC), and the “Réseau français des biobanques des tumeurs hépatiques.”


    Abstract


Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). However, very little is known about the replication of HBV in HCC tissues. We analyzed viral and cellular parameters in HCC (T) and nontumor liver (NT) samples from 99 hepatitis B surface antigen (HBsAg)-positive, virologically suppressed patients treated by tumor resection or liver transplantation. We examined total HBV DNA and RNA as well as covalently closed circular DNA (cccDNA) and pregenomic RNA (pgRNA), which are considered as markers of active HBV replication. Total HBV DNA and RNA were detected in both T and NT samples in a majority of cases, but only a subset of tumors harbored detectable levels of HBV cccDNA and pgRNA (39% and 67%) compared to NT livers (66% and 90%; P < 0.01). Further evidence for HBV replication in tumor tissues was provided by sequencing of the X gene derived from episomal forms, showing that HBV genotypes differed between T and matched NT samples in 11 cases. The detection of pgRNA and cccDNA in tumors was correlated to the absence of tumorous microvascular invasion and to better patient survival. Analysis of gene expression profiles by Agilent microarrays revealed that pgRNA-positive HCCs were characterized by low levels of cell cycle and DNA repair markers and expression of the HBV receptor, sodium taurocholate cotransporting polypeptide, indicating well-differentiated tumors. Conclusion: HCC replicating HBV represents a subtype of weakly invasive HCC with a transcriptomic signature. pgRNA originating from nonintegrated, complete HBV genomes is a sensitive marker for viral replication and prognosis. (Hepatology 2018;67:86-96).

StephenW

乙型肝炎病毒前基因组RNA在肝细胞癌：A Nosological and Prognostic Determinants

Boris Halgand1 Christophe Desterke2 LiseRivière3Guillaume Fallot2MylèneSebagh2 Julien Calderaro4 Paulette Bioulac-Sage5 Christine Neuveut3 Marie-Annick Buendia2 Didier Samuel2和Cyrille Frayray4 *

在线记录版本：2017年12月19日

DOI：10.1002 / hep.29463

©2017由美国肝病研究协会。


肝病

第67卷，第1期，第86-96页，2018年1月
文章的对等评分为1

1 INSERM U948，法国南特市，南德法国妇女研究所
2法国巴黎南大学INSERM U1193，法国维勒瑞夫保罗布鲁斯医院
3UnitéHepacivirus etImmunitéInnée，CNRS URA 3015，法国巴黎巴斯德研究所
法国CréteilHenri Mondor医院的INSERM U955，Paris-Est-Créteil大学
法国波尔多Bordeaux 2大学INSERM U1053 CHU波尔多5病理学系

电子邮件：CyrilleFéray（[email protected]）

*地址通讯和重印请求：
CyrilleFéray，M.D.博士
INSERM-U955，Henri Mondor研究所
大街du Marchacha de Lattre de Tassigny
94010Créteil，法国
电子邮件：[email protected]
电话：33（0）149812123

潜在的利益冲突：Samuel博士为Astellas，Bristol-Myers Squibb，Gilead，LFB，MSD，Roche，Biotest，AbbVie和Intercept提供咨询。

（ANRS），“国家癌症研究所”（INCA），“癌症研究协会”（ARC）和“Réseaufrançais”（PAIRINCA CHC，2009年） des biobanques des tumeurshépatiques“。


抽象


然而，关于HBV在HCC组织中的复制知之甚少。我们分析了99例乙肝表面抗原（HBsAg）阳性，病毒学抑制的肿瘤切除或肝移植患者的HCC（T）和非肿瘤肝（NT）样本中的病毒和细胞参数。我们检测了总HBV DNA和RNA以及被认为是活跃HBV复制标记物的共价闭合环状DNA（cccDNA）和前基因组RNA（pgRNA）。在大多数情况下，在大多数T和NT样品中均检测到总HBV DNA和RNA，但与NT相比，仅一部分肿瘤含有可检测水平的HBV cccDNA和pgRNA（39％和67％）。通过对来自附加型的X基因进行测序来提供肿瘤组织，显示在11例中T和匹配的NT样品之间HBV基因型不同。检测肿瘤中pgR NAc和cccDNA的肝脏（66％和90％; P <0.01）与没有肿瘤微血管浸润和更好的患者存活相关。通过安捷伦微阵列分析基因表达谱显示，pgRNA阳性HCC的特征在于低水平的细胞周期和DNA修复标志物和HBV受体，牛磺胆酸钠共转运多肽的表达，表明分化良好的肿瘤。结论：HCC复制HBV是一种具有转录组学特征的微弱HCC亚型。来源于非整合的完整HBV基因组的PgRNA是病毒复制和预后的敏感标记。 （Hepatology 2018; 67：86-96）。