Hepatocellular carcinoma

Abstract

The hepatitis B virus (HBV) is a widespread human pathogen that causes liver inflammation, cirrhosis, and hepatocellular carcinoma (HCC). Recent sequencing technologies have refined our knowledge of the genomic landscape and pathogenesis of HCC, but the mechanisms by which HBV exerts its oncogenic role remain controversial. In a prevailing view, inflammation, liver damage, and regeneration may foster the accumulation of genetic and epigenetic defects leading to cancer onset. However, a more direct and specific contribution of the virus is supported by clinical and biological observations. Among genetically heterogeneous HCCs, HBV-related tumors display high genomic instability, which may be attributed to the ability of HBV to integrate its DNA into the host cell genome, provoking chromosomal alterations and insertional mutagenesis of cancer genes. The viral transactivator HBx may also participate in transformation by deregulating diverse cellular machineries. A better understanding of the complex mechanisms linking HBV to HCC will improve prevention and treatment strategies.

Figure 1.

Hepatocellular carcinoma: risk factors and progression of liver disease at preneoplastic and neoplastic stages. As with all cancers, hepatocellular carcinoma (HCC) develops in a stepwise fashion with sequential acquisition of premalignant and malignant characters. During chronic hepatitis, liver injury is caused by persistent inflammation and oxidative stress, which provoke repeated cycles of apoptosis, necrosis, and compensatory regeneration. High-grade cirrhotic nodules (the immediate precursors of HCC) frequently show TERT promoter mutations, chromosomal aberrations, and epigenetic silencing of tumor suppressor genes. HCCs can also develop on a background of hepatitis with various degrees of fibrosis in ∼20% of cases, mostly in hepatitis B virus (HBV) carriers. HCV, hepatitis C virus. (Courtesy of Catherine Guettier, INSERM U785, Pathology Department, Paul Brousse Hospital.)

Figure 2.

HBV DNA integration in human HCC: recurrent cellular targets and viral breakpoints. Data were deduced from published whole-genome sequencing studies covering ∼200 tumors and matched nontumor liver tissues. (Top) Integrations into TERT promoter and introns (Fujimoto et al. 2012; Jiang et al. 2012; Sung et al. 2012; Toh et al. 2013; Li et al. 2014). Hot-spot somatic mutations in the TERT promoter are shown with arrows below the figure (Nault et al. 2013). (Bottom) Distribution on the HBV genome of viral sites found frequently at the virus–host junctions, showing preferential integration near the DR1 repeat within the 3′ end of the X gene. The arrows represent the viral genes, and positions are numbered from the EcoR1 site. Chr, chromosome.

Figure 3.

Insertional activation of Myc family genes in woodchuck hepatitis virus (WHV)-induced woodchuck HCCs. WHV insertion sites into the c-myc and N-myc2 loci are shown with arrows, and preferred integration sites of retroviruses including murine leukemia virus (MLV), feline leukemia virus (FeLV), avian leukemia virus (ALV), and avian reticuloendotheliosis virus (REV) are mapped under c-myc. The b3n and win loci are located 10 and 180 kb downstream from N-myc2 on the woodchuck X chromosome, and viral integration in these loci leads to N-myc2 activation. Percentages of WHV integration at each locus in a panel of 70 woodchuck tumors analyzed are shown on the left. chr., chromosome.