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.作者: StephenW 时间: 2021-2-16 18:05
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