title: Impact of hepatitis B virus (HBV) x gene mutations on hepatocellular carcinoma development in chronic HBV infection.
abstract: The hepatitis B virus (HBV) PreS mutations C1653T, T1753V, and A1762T/G1764A were reported as a strong risk factor of hepatocellular carcinoma (HCC) in a meta-analysis. HBV core promoter overlaps partially with HBx coding sequence, so the nucleotide 1762 and 1764 mutations induce HBV X protein (HBx) 130 and 131 substitutions. We sought to elucidate the impact of HBx mutations on HCC development. Chronically HBV-infected patients were enrolled in this study: 42 chronic hepatitis B (CHB) patients, 23 liver cirrhosis (LC) patients, and 31 HCC patients. Direct sequencing showed HBx131, HBx130, HBx5, HBx94, and HBx38 amino acid mutations were common in HCC patients. Of various mutations, HBx130+HBx131 (double) mutations and HBx5+HBx130+HBx131 (triple) mutations were significantly high in HCC patients. Double and triple mutations increased the risk for HCC by 3.75-fold (95% confidence interval [CI] = 1.101 to 12.768, P = 0.033) and 5.34-fold (95% CI = 1.65 to 17.309, P = 0.005), respectively, when HCC patients were compared to CHB patients. Functionally, there were significantly higher levels of NF-κB activity in cells with the HBx5 mutant and with the double mutants than that of wild-type cells and the triple-mutant cells. The triple mutation did not increase NF-κB activity. Other regulatory pathways seem to exist for NF-κB activation. In conclusion, a specific HBx mutation may contribute to HCC development by activating NF-κB activity. The HBx5 mutation in genotype C2 HBV appears to be a risk factor for the development of HCC and may be used to predict the clinical outcomes of patients with chronic HBV infection.
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, 250 Seongsan-no, Seodaemun-gu, Seoul 120-752, Korea.
authors.forename: Jong-Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
authors.forename: Jae Myun
authors.initials: JM
authors.lastname: Lee
authors.forename: Jeon Han
authors.initials: JH
authors.lastname: Park
authors.forename: Hyon-Suk
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D005260:Female; D006515:Hepatitis B virus / Q000235:genetics* / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016328:NF-kappa B / Q000096:biosynthesis; D015534:Trans-Activators / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins; D037521:Virulence Factors / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D037521:Virulence Factors; C057628:hepatitis B virus X protein