PT  - JOURNAL ARTICLE
AU  - Camille Péneau
AU  - Sandrine Imbeaud
AU  - Tiziana La Bella
AU  - Theo Z Hirsch
AU  - Stefano Caruso
AU  - Julien Calderaro
AU  - Valerie Paradis
AU  - Jean-Frederic Blanc
AU  - Eric Letouzé
AU  - Jean-Charles Nault
AU  - Giuliana Amaddeo
AU  - Jessica Zucman-Rossi
TI  - Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma
AID  - 10.1136/gutjnl-2020-323153
DP  - 2022 Mar 01
TA  - Gut
PG  - 616--626
VI  - 71
IP  - 3
4099  - http://gut.bmj.com/content/71/3/616.short
4100  - http://gut.bmj.com/content/71/3/616.full
SO  - Gut2022 Mar 01; 71
AB  - 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.Data are available in a public, open access repository. The sequencing data of the LICA-FR cohort reported in this paper have been deposited to the European Genome-phenome Archive (EGA) database (RNA-seq fastq files accessions (EGAS00001001284), (EGAS00001002879), (EGAS00001003310), (EGAS00001003837) and (EGAS00001004629); WES bam files accessions (EGAS00001000217), (EGAS00001001002), (EGAS00001003063), (EGAS00001003130), (EGAS00001003837) and (EGAS00001004629); WGS bam files accessions (EGAS00001000706), (EGAS00001002408), (EGAS00001002888), (EGAS00001003063), (EGAS00001003837) and (EGAS00001004629), through the International Cancer Genome Consortium (ICGC) data access committee. Data are available for reuse and can be consulted at the following address: https://ega-archive.org/studies/EGASxxx with access permission from ICGC Data Access Compliance Office.