title: Novel point and combo-mutations in the genome of hepatitis B virus-genotype D: characterization and impact on liver disease progression to hepatocellular carcinoma.
abstract: BACKGROUND
  The contribution of chronic hepatitis B virus (HBV) infection in the pathogenesis of hepatocellular carcinoma (HCC) through progressive stages of liver fibrosis is exacerbated by the acquisition of naturally occurring mutations in its genome. This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naïve Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC.
  
  
  METHODS
  The mutation profile was determined from the sequence analysis of the full-length HBV genome and compared with the reference HBV sequences. SPSS 16.0 and R software were used to delineate their statistical significance in predicting HCC occurrence.
  
  
  RESULTS
  Age was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p ≤ 0.01). Beyond the classical mutations in basal core promoter (BCP) (A1762T/G1764A) and precore (G1862T), persistence of progressively accumulated mutations in enhancer-I, surface, HBx and core were showed significant association to liver disease progression. BCP_T1753C, core_T147C, surface_L213I had contributed significantly in the disease progression to HCC (p < 0.05) in HBeAg positive patients whereas precore_T1858C, core_I116L, core_P130Q and preS1_S98T in HBeAg negative patients. Furthermore, the effect of individual mutation was magnified by the combination with A1762T/G1764A in HCC pathogenesis. Multivariate risk analysis had confirmed that core_P130Q [OR 20.71, 95% CI (1.64-261.77), p = 0.019] in B cell epitope and core_T147C [OR 14.58, 95% CI (1.17-181.76), p = 0.037] in CTL epitope were two independent predictors of HCC in HBeAg positive and negative patients respectively.
  
  
  CONCLUSIONS
  Thus distinct pattern of mutations distributed across the entire HBV genome may be useful in predicting HCC in high-risk CHB patients and pattern of mutational combinations may exert greater impact on HCC risk prediction more accurately than point mutations and hence these predictors may support the existing surveillance strategies in proper management of the patients.
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Somenath
authors.initials: S
authors.lastname: Datta
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Alip
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Debanjali
authors.initials: D
authors.lastname: Dasgupta
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Shrabasti
authors.initials: S
authors.lastname: Roychoudhury
authors.affiliation: Molecular Virology Laboratory, Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Roy
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Soumyojit
authors.initials: S
authors.lastname: Das
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Kausik
authors.initials: K
authors.lastname: Das
authors.affiliation: Centre for Liver & Biliary Surgery, Indraprastha Apollo Hospital, New Delhi, India.
authors.forename: Subash
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Keya
authors.initials: K
authors.lastname: Basu
authors.affiliation: National Institute of Biomedical Genomics, Kalyani, India.
authors.forename: Analabha
authors.initials: A
authors.lastname: Basu
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Simanti
authors.initials: S
authors.lastname: Datta
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Soma
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology*; D004279:DNA, Viral; D018450:Disease Progression; D005260:Female; D016679:Genome, Viral; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000473:pathology / Q000821:virology; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology*; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
chemical_list: D004279:DNA, Viral