HBV is responsible for over 50% of HCCs; the second cause of cancer death worldwide.
ReviewMechanisms of HBV-induced hepatocellular carcinoma
Introduction
Hepatocellular carcinoma (HCC) represents, with an estimated 500,000–600,000 deaths/year [1], [2], the second cause of cancer death worldwide [3]. HCC development is driven by the interaction of genetic predisposition, environmental factors (metabolic syndrome, alcohol, aflatoxin B1, aristocholic acid) and viruses (hepatitis B virus (HBV), hepatitis C virus (HCV)). Despite the establishment of HBV vaccine programs since the early 90s, the decreased incidence of HBV new infections in many countries and the availability of potent antiviral treatments that lead to long-term inhibition of HBV replication, 240 million people are chronically infected with HBV and remain at risk of developing liver cirrhosis and HCC [2], [3].
Driving forces in hepatocyte transformation, HCC development and progression are chronic inflammation, DNA damage, epigenetic modifications, senescence and telomerase reactivation, chromosomal instability and early neo-angiogenesis. Although most HCCs develop in the context of liver cirrhosis, which is recognized as a pro-carcinogenic field, HCC can also develop in non-cirrhotic livers. All “etiologic” factors seem to act through similar mechanisms (i.e. point mutations, chromosomal aberrations, epigenetic changes) that converge to affect common pathways. Notably, mutations and chromosomal aberrations have been predominantly found in benign and malignant tumor tissues whereas the dysregulation of signaling pathways and epigenetic changes are also detected earlier in the natural history of HCC development, at the stage of cirrhosis. In the last 10 years, genome-wide technologies and next generation sequencing (NGS) have enabled the identification of molecular signatures to classify subgroups of HCCs and stratify patients according to prognosis, and have highlighted the role of pathways previously underexplored in the HCC field, such as chromatin remodeling and autophagy. The molecular pathogenesis and classification of HCCs and their impact on the design of new therapeutic approaches has been the object of several recent and comprehensive reviews [4], [5], [6], [7], [8]. Here, we focus on the molecular characterization of HBV-related carcinomas, the contribution of HBV genetic variability, HBV integration into the host genome and wild-type and mutated/truncated viral proteins to HCC development.
Section snippets
Epidemiology and co-factors
Recent estimates attribute over 50% of HCC cases worldwide to HBV [1], [2], making it the most common carcinogen after tobacco. The role of HBV in HCC may be greater than that depicted by sero-epidemiologic studies, as suggested by the increased risk of developing HCC in patients with occult HBV infection (defined as persistence of free and/or integrated forms of HBV DNA in the liver in the absence of the viral marker HBsAg in the serum [9]) and after hepatitis B surface antigen (HBsAg)
HBV life cycle, viral heterogeneity and HCC
HBV genomic variability is attributed to lack of proof-reading by the HBV polymerase and the high copy number of the virus. This leads to the selection of HBV quasi-species containing several mutations; some providing a replicative advantage to the virus while others are detrimental. Circulating infectious HBV particles contain a circular partially double-stranded DNA of about 3200 nucleotides [20]. Soon after
The genetic/epigenetic landscape of HBV-related HCC
HBV contributes to HCC development through direct and indirect mechanisms.
Extensive evidence indicates that HCC is an extremely heterogeneous tumor at the genetic and molecular level, with a complex mutational landscape and multiple transcription and signaling pathways involved [8] (Fig. 1).
Direct oncogenic roles of HBV
HBV can promote carcinogenesis by three different mechanisms: a) a classic retrovirus-like insertional mutagenesis with the integration of viral DNA into host cancer genes like TERT, CCNE1, and MLL4; b) the promotion of genomic instability as the result of both the integration of viral DNA into the host genome and the activity of viral proteins; c) the ability of wild-type and mutated/truncated viral proteins (HBx, HBc and preS) to affect cell functions, activate oncogenic pathways and
Conclusions
HBV is a major risk factor worldwide for developing HCC and contributes to HCC development through direct and indirect mechanisms. Productive HBV infections trigger inflammation and continuous necrosis mediated by the immune response against infected hepatocytes. Compensatory proliferation of adult hepatocytes as well as of the bipotential hepatobilliary progenitors acting as facultative stem cells and residing in bile canaliculi (hepatic progenitor cells (HPCs) in humans, oval cells in
Financial support
JZR has grants from the Ligue contre le Cancer – France, INCa (Institut National du Cancer) ICGC Project – France; ANRS (Agence National de Recherche sur le SIDA et les Hepatities Virales) – France; ANR (Agence National de la Recherche) – France; PALSE (Package d’Accueil Lyon Saint Etienne) – France; EC Horizon 2020 (HepCar Project n. 667273).
Conflict of interest
These authors disclose the following: JZR is consultant for IntraGen. ML received consulting honoraria from Gilead, BMS, Assembly, Arbutus, Janssen, Medimmune, Galapagos.
Author contributions
ML and JZR participated in all stages of manuscript production, design, figures, tables, writing, and review of final version.
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