Viral mutations and host diversities that contribute to hepatocarcinogenesis

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The natural history of hepatitis virus infection consists of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). However, the factors influencing disease progression to HCC have not been well elucidated. Here, we studied viral mutations and host diversities that contribute to hepatocarcinogenesis. 1) WBC DNAs were extracted from sera of 1.000 patients with hepatitis 13/C after obtaining written informed consent, and data base containing clinical data of these patients were constructed. Then, WBC DNA samples of 500 patients were anonymized by the method we established. 2) By analyzing hepatitis B virus (HBV) X gene nucleotide sequence in patients with/without HOC, it was revealed that amino acid substitution in codon 38 in HBx is significantly related with HOC. 3) Amino acid changes in C-terminal hydrophobic region of hepatitis C virus (HCV) core were observed more frequently in the interferon biological responders (BR) compared to interferon noivresponders (NR). Activatio … More n of Interleukin (IL)-8 promoter by core proteins significantly decreased after interferon therapy in the BR group compared to the NR group. Differences in amino acid sequence of HCV core possibly correlate with hepatitis activity by modulating IK-8 induction in HCV infected patients. 4) The effect of HCV core protein, HBx protein, and hepatitis delta virus large antigen on intracellular signaling pathway was determined. 5) Genetic polymorphsims of uidine 5'-diphosphate-glucuronosyltransferase 1A7 (UGT 1A7) and 1L-1β were investigated in 280 Japanese patients (122 with HCC) with chronic HCV infections. The proportions of UCT1A7 low activity allele (L)/L and high activity allel (H)/L in patients with HOC (25% and 45%, respectively) were higher than those in patients without HOC (15% and 39%, respectively) with an odds ratio of 2.7 and 1.8, respectively, comared with the UGT1A7 H/H. The IL-1β/-31 T/T genotype showed a significant association with the presence of HOC compared with the C/C genotype with an odds ratio of 2.9. 6) To search of single nucleotide polymorphisms(SNPs) for HOC susceptibility genes, 394 SNPs derived from 172 candidate genes were examined in 376 Japanese patients (including 170patients with HOC) with chronic HCV infection. Three SNPs derived from three genes were significantly associated with HOC. These SNPs and haplotypes will be used as markers to identify a subgroup at higher risk of HOC in Japanese patients with chronic HCV infection. Less