Host and Viral Genetic Variation in HBV-Related Hepatocellular Carcinoma

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.

Integrative analysis of highly mutated genes in hepatitis B virus‐related hepatic carcinoma

“…Based on KEGG pathways, we discovered that significant pathways were related to different cancers, indicating that these identified mutated genes might play critical roles in the development of multiple types of cancers. The mutated genes associated with Wnt signaling pathways and cell cycle pathways have been reported to facilitate the development of HCC . Consistent with published studies, based on WIKI pathways, we found that the pathways related to Wnt signaling and cell cycle were enriched by the identified mutated genes in HBV‐related HCC.…”

“…HBV infection could cause genomic instability, including mutation and epigenetic misregulation in genes, and multiple mechanisms are involved in gene mutation mediated by the virus. For example, HBV is capable of interfering with the function of mitotic regulatory proteins and mitotic spindle checkpoint proteins, which have the role of maintaining genomic integrity . The virus could integrate the viral genome into the host DNA to induce genetic alterations .…”

“…Hepatocellular carcinoma (HCC), the major pathological type of liver cancer, is still a leading cause of cancer‐related death worldwide . In Asia and Africa, chronic hepatitis B virus (HBV) infection is the major cause of HCC development . Although it has been suggested that several factors, including the repeated inflammation mediated by immune reactions against the virus, the integration of HBV DNA into the host genome and the virus‐encoded oncoproteins (HBx and preS2/S proteins), are responsible for the development of HCC induced by HBV infection, the molecular mechanisms of hepatocarcinogenesis caused by HBV infection are still not well understanding, and no effective agents have been developed for the treatment of HBV‐related HCC.…”

“…Accumulation of genetic alterations is a hallmark of HCC, and a great number of mutated genes, including CTNNB1, TSC1/2, PREX2, TP53, TERT, AXIN1, ARID1A, RET, and ARID2, have been identified in HCC, especially, in HBV‐related HCC . Current studies suggest that the mutations of CTNNB1 are associated with low stage HCC .…”

“…1 In Asia and Africa, chronic hepatitis B virus (HBV) infection is the major cause of HCC development. [2][3][4] Although it has been suggested that several factors, [5][6][7] including the repeated inflammation mediated by immune reactions against the virus, the integration of HBV DNA into the host genome and the virus-encoded oncoproteins (HBx and preS2/S proteins), are responsible for the development of HCC induced by HBV infection, the molecular mechanisms of hepatocarcinogenesis caused by HBV infection are still not well understanding, and no effective agents have been developed for the treatment of HBV-related HCC. Hence, it is extremely important to discover novel molecules involved in the carcinogenesis of HBV-associated HCC and offer the possibility of improving therapeutic approaches for HCC with HBV infection.…”