Host and Viral Genetic Variation in HBV-Related Hepatocellular Carcinoma - PubMed (original) (raw)

Review

Ping An et al. Front Genet. 2018.

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the second leading cause of cancer deaths globally. The high prevalence of HCC is due in part to the high prevalence of chronic HBV infection and the high mortality rate is due to the lack of biomarkers for early detection and limited treatment options for late stage HCC. The observed individual variance in development of HCC is attributable to differences in HBV genotype and mutations, host predisposing germline genetic variations, the acquisition of tumor-specific somatic mutations, as well as environmental factors. HBV genotype C and mutations in the preS, basic core promoter (BCP) or HBx regions are associated with an increased risk of HCC. Genome-wide association studies have identified common polymorphisms in KIF1B, HLA-DQ, STAT4, and GRIK1 with altered risk of HBV-related HCC. HBV integration into growth control genes (such as TERT), pro-oncogenic genes, or tumor suppressor genes and the oncogenic activity of truncated HBx promote hepatocarcinogenesis. Somatic mutations in the TERT promoter and classic cancer signaling pathways, including Wnt (CTNNB1), cell cycle regulation (TP53), and epigenetic modification (ARID2 and MLL4) are frequently detected in hepatic tumor tissues. The identification of HBV and host variation associated with tumor initiation and progression has clinical utility for improving early diagnosis and prognosis; whereas the identification of somatic mutations driving tumorigenesis hold promise to inform precision treatment for HCC patients.

Keywords: genotype; hepatitis B virus; hepatocellular carcinoma; mutation; single nucleotide polymorphisms.

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Figures

Figure 1

Figure 1

Viral and host genetic factors involved in the development of HBV-induced HCC. HBV infection, if not resolved, may develop to chronic hepatitis and progress to liver cirrhosis and subsequently HCC. Molecular mechanisms of HBV-related HCC involve (1) chronic inflammation and regeneration of hepatocytes; (2) accumulation of genetic alterations that confer cell growth advantage; (3) integration of HBV DNA into the host genome and activation of host genes controlling cell proliferation; (4) genomic instability; and (5) direct promotion of cell proliferation by viral proteins (mainly HBx). The development of HCC is the consequence of the interaction of environmental factors (e.g., aflatoxin), HBV viral factors (genotypes, HBV DNA levels and HBV mutants) and host genetic susceptible variants (e.g., HLA-DP variants affecting HBV clearance), along with somatic mutations (TP53, TERT, gene deletion/amplification) disrupting cell growth control. HBV genotype C and mutations in the preS, basic core promoter or HBx gene are associated with an increased risk of HCC.

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