乙型肝炎病毒整合促进肝细胞癌的局部和远距离致癌驱动因

StephenW

Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma

    http://orcid.org/0000-0002-5479-1288Camille Péneau1,2, http://orcid.org/0000-0001-8439-6732Sandrine Imbeaud1,2, Tiziana La Bella1,2, http://orcid.org/0000-0003-4428-2997Theo Z Hirsch1,2, Stefano Caruso1,2, Julien Calderaro3, Valerie Paradis4,5, Jean-Frederic Blanc6,7,8, Eric Letouzé1,2, http://orcid.org/0000-0002-4875-9353Jean-Charles Nault1,2,9, Giuliana Amaddeo10, http://orcid.org/0000-0002-5687-0334Jessica Zucman-Rossi1,2,11

Author affiliations

    Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France
    Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France
    Service d’Anatomopathologie, Hôpital Henri Mondor, APHP, Institut Mondor de Recherche Biomédicale, Créteil, France
    Service de Pathologie, Hôpital Beaujon, APHP, Clichy, France
    Université Paris Diderot, CNRS, Centre de Recherche 27 sur l'Inflammation (CRI), Paris, France
    Service Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, Bordeaux, France
    Service de Pathologie, CHU Bordeaux GH Pellegrin, Bordeaux, France
    Université Bordeaux, Inserm, Research in Translational Oncology, BaRITOn, Bordeaux, France
    Service d’Hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, Bobigny, France
    Service d’Hépato-Gastro-Entérologie, Hôpital Henri Mondor, APHP, Université Paris Est Créteil, Inserm U955, Institut Mondor de recherche biomedicale, Creteil, Île-de-France, France
    Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Correspondence to Professor Jessica Zucman-Rossi, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, INSERM, Paris 75006, France; [email protected]

Abstract

Objective Infection by HBV is the main risk factor for hepatocellular carcinoma (HCC) worldwide. HBV directly drives carcinogenesis through integrations in the human genome. This study aimed to precisely characterise HBV integrations, in relation with viral and host genomics and clinical features.

Design A novel pipeline was set up to perform viral capture on tumours and non-tumour liver tissues from a French cohort of 177 patients mainly of European and African origins. Clonality of each integration event was determined with the localisation, orientation and content of the integrated sequence. In three selected tumours, complex integrations were reconstructed using long-read sequencing or Bionano whole genome mapping.

Results Replicating HBV DNA was more frequently detected in non-tumour tissues and associated with a higher number of non-clonal integrations. In HCC, clonal selection of HBV integrations was related to two different mechanisms involved in carcinogenesis. First, integration of viral enhancer nearby a cancer-driver gene may lead to a strong overexpression of oncogenes. Second, we identified frequent chromosome rearrangements at HBV integration sites leading to cancer-driver genes (TERT, TP53, MYC) alterations at distance. Moreover, HBV integrations have direct clinical implications as HCC with a high number of insertions develop in young patients and have a poor prognosis.

Conclusion Deep characterisation of HBV integrations in liver tissues highlights new HBV-associated driver mechanisms involved in hepatocarcinogenesis. HBV integrations have multiple direct oncogenic consequences that remain an important challenge for the follow-up of HBV-infected patients.

StephenW

乙型肝炎病毒整合促进肝细胞癌的局部和远距离致癌驱动因子改变

    http://orcid.org/0000-0002-5479-1288CamillePéneau1,2，http：//orcid.org/0000-0001-8439-6732Sandrine Imbeaud1,2，Tiziana La Bella1,2，http：// orcid。 org / 0000-0003-4428-2997 Theo Z Hirsch1,2，Stefano Caruso1,2，Julien Calderaro3，Valerie Paradis4,5，Jean-Frederic Blanc6,7,8，EricLetouzé1,2，http://orcid.org/0000 -0002-4875-9353Jean-Charles Nault1,2,9，Giuliana Amaddeo10，http：//orcid.org/0000-0002-5687-0334Jessica Zucman-Rossi1,2,11

作者单位

    法国巴黎索邦大学，法国巴黎大学索德分校中心
    实体肿瘤功能基因组学实验室，法国Labex OncoImmunology的国家癌症研究实验室，法国巴黎
    法国，克雷泰伊，Redorche生物医学研究所，APHP，HôpitalHenri Mondor，Anatomopathologie服务
    法国，克利希，APHP，HôpitalBeaujon，Pathologie服务
    巴黎迪德罗特大学，CNRS，炎症中心27日，法国巴黎
    法国波尔多CHU de Bordeaux的HôpitalHaut-LévêqueHépato-Gastroentérologieet Oncologie Digestive服务
    法国波尔多CHU Bordeaux GH Pellegrin的Pathologie服务处
    波尔多大学，Inserm，转化肿瘤学研究，BaRITOn，法国波尔多
    巴黎塞纳-圣但尼大学高等学院，HôpitalAvicenne服务中心，APHP，法国波比尼
    d'Hépato-Gastro-Entérologie服务，HôpitalHenri Mondor，APHP，Paris EstCréteil大学，Inserm U955，Mondor de recherche生物医学研究所，Creteil，法国法兰西岛
    HôpitalEuropéenGeorges Pompidou，AP-HP，法国巴黎

    通讯作者：法国巴黎INSPERM巴黎Inserm索邦大学，法国谢赫科德莱尔中心的Jessica Zucman-Rossi教授；法国巴黎75006； [email protected]

抽象的

目的HBV感染是全世界肝细胞癌（HCC）的主要危险因素。 HBV通过整合人类基因组直接驱动癌变。这项研究旨在准确表征与病毒和宿主基因组学及临床特征相关的HBV整合。

设计建立了一条新的管道，以对来自法国的177名主要来自欧洲和非洲血统的患者的肿瘤和非肿瘤肝组织进行病毒捕获。每个整合事件的克隆性由整合序列的定位，方向和内容确定。在三个选定的肿瘤中，使用长读测序或Bionano全基因组图谱重建了复杂的整合体。

结果在非肿瘤组织中检测到复制HBV DNA的频率更高，并且与大量非克隆整合相关。在HCC中，HBV整合的克隆选择与致癌过程涉及的两种不同机制有关。首先，在癌症驱动基因附近整合病毒增强剂可能导致癌基因强烈表达。其次，我们在HBV整合位点发现频繁的染色体重排，导致远处的癌症驱动基因（TERT，TP53，MYC）发生改变。此外，由于年轻患者中发生大量插入的HCC，且预后较差，因此HBV整合具有直接的临床意义。

结论肝组织中HBV整合的深入表征突显了与肝癌发生有关的新HBV相关驱动程序机制。 HBV整合具有多种直接的致癌作用，这对于HBV感染患者的随访仍然是一项重要挑战。

StephenW

https://gut.bmj.com/content/gutj ... 020-323153.full.pdf