Host and Viral Genetic Variation in HBV-Related Hepatocellular Carcinoma.

Ping An,Jinghang Xu,Cheryl A Winkler,Yanyan Yu

doi:10.3389/fgene.2018.00261

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.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the second leading cause of cancer deaths worldwide (El-Serag, 2011; Torre et al, 2015)
The clinical spectrum of chronic Hepatocellular CarcinomaHepatitis B virus (HBV) infection ranges from asymptomatic carrier status to chronic hepatitis B (CHB), which may evolve to liver cirrhosis and HCC (EASL, 2012)
telomerase reverse transcriptase (TERT) promoter mutations are the most frequent somatic genetic alterations observed in HCC, with an overall prevalence of approximately 60%, with ranges from 30 to 40% for HBVrelated HCC to 60 to 80% for hepatitis C virus (HCV)-related HCC (Nault et al, 2013; Totoki et al, 2014; Fujimoto et al, 2015; Schulze et al, 2015; Kawai-Kitahata et al, 2016; Yang et al, 2016a)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the second leading cause of cancer deaths worldwide (El-Serag, 2011; Torre et al, 2015). Major HBV viral factors associated with increased risk of HCC include genotype C and F, higher HBVDNA levels, mutations in the preS/S region, the double mutation A1762T/G1764A in the basic core promoter, and the double or triple mutation K130M, V131I xV5M in the HBx gene.

Results

Conclusion