Abstract
BackgroundHepatitis B virus (HBV) is the major risk factor for hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV-associated HCC pathogenesis is still unclear. Genetic alterations in cancer-related genes have been linked to many human cancers. Here, we aimed to explore genetic alterations in selected cancer-related genes in patients with HBV-associated HCC.MethodsTargeted sequencing was used to analyze six cancer-related genes (PIK3CA, TP53, FAT4, IRF2, HNF4α and ARID1A) in eight pairs of HBV-associated HCC tumors and their adjacent non-tumor tissues. Sanger sequencing, quantitative PCR, Western-blotting and RNAi-mediated gene knockdown were used to further validate findings.ResultsTargeted sequencing revealed thirteen non-synonymous mutations, of which 9 (69%) were found in FAT4 and 4 (31%) were found in TP53 genes. Non-synonymous mutations were not found in PIK3CA, IRF2, HNF4α and ARID1A. Among these 13 non-synonymous mutations, 12 (8 in FAT4 and 4 in TP53) were predicted to have deleterious effect on protein function by in silico analysis. For TP53, Y220S, R249S and P250R non-synonymous mutations were solely identified in tumor tissues. Further expression profiling of FAT4 and TP53 on twenty-eight pairs of HCC tumor and non-tumor tissues confirmed significant downregulation of both genes in HCC tumors compared with their non-tumor counterparts (P < 0.001 and P < 0.01, respectively). Functional analysis using RNAi-mediated knockdown of FAT4 revealed an increased cancer cell growth and proliferation, suggesting the putative tumor suppressor role of FAT4 in HCC.ConclusionsThis study highlights the importance of FAT4 and TP53 in HCC pathogenesis and identifies new genetic variants that may have potentials for development of precise therapy for HCC.
Highlights
Hepatitis B virus (HBV) is the major risk factor for hepatocellular carcinoma (HCC)
13 (22.8%) were non-synonymous somatic mutations, 31 (54.4%) were insertions/deletions and 13 (22.8%) were synonymous mutations (Fig. 1 and Additional files 5, 6, 7: Table S5–7). 70% (40/57) of these mutations were indexed in the single nucleotide polymorphism database and 75% (9/13) of the non-synonymous mutations were listed in the Catalogue Of Somatic Mutations In Cancer (COSMIC) database
We focused on FAT atypical cadherin 4 (FAT4) and TP53 genes as both showed frequent nonsynonymous mutations in our targeted sequencing cohort
Summary
Hepatitis B virus (HBV) is the major risk factor for hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV-associated HCC pathogenesis is still unclear. We aimed to explore genetic alterations in selected cancerrelated genes in patients with HBV-associated HCC. Most cases of HCC are associated with chronic infection of hepatitis B virus (HBV) and/or hepatitis C virus (HCV). Other factors such as alcohol consumption, smoking, aflatoxin B exposure, diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD) may act either as amplifiers of the effects of viral hepatitis or as independent risk factors of HCC [3]. It is necessary to identify genomic alterations underlying the pathogenesis of HCC to pinpoint efficient therapeutic targets for early diagnosis and treatment of this deadly disease, as well as to improve its prognosis in affected patients [5]
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