title: Evolutionary Changes of Hepatitis B Virus Pre-S Mutations Prior to Development of Hepatocellular Carcinoma.
abstract: OBJECTIVE
  Deletions/mutations in the hepatitis B virus (HBV) pre-S region have been associated with hepatocellular carcinoma (HCC). We aimed to study the evolutionary changes of pre-S mutations prior to HCC development.
  
  
  METHODS
  We studied the HBV pre-S sequences at 1 to 10 years preceding diagnosis of HCC in 74 patients with HBV-related HCC (HCC group). 148 chronic hepatitis B patients matched for sex and age in 2:1 ratio, who had been followed up for at least 3 years without HCC (HCC-free group) were recruited as controls. 56 and 47 patients of HCC and HCC-free groups respectively had serially stored sera for longitudinally examination at 1-3 years, 4-6 years, 7-9 years and ≥10 years prior to the recruitment of the study.
  
  
  RESULTS
  Compared to the HCC-free group, higher frequencies of pre-S deletions and point mutations (at 11 codons) were observed in the HCC group (p<0.05). Multiple logistic regression analysis showed that pre-S deletions, point mutations at codon 51 and 167 were independent factors associated with HCC. Longitudinal observation showed that pre-S deletions and most of the 11 HCC-associated pre-S point mutations existed at least 10 years before HCC development, and were more prevalent preceding HCC development in patients from HCC groups than HCC-free group. The number of HCC-associated pre-S point mutations increased over time preceding HCC development, and correlated positively with the time to HCC diagnosis (r = 0.220, p = 0.005).
  
  
  CONCLUSIONS
  High prevalence and cumulative evolution of pre-S mutations preceding HCC development suggested a possible carcinogenic role of pre-S mutations and their potential application in HCC risk prediction.
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: An-Ye
authors.initials: AY
authors.lastname: Zhang
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Fung-Yu
authors.initials: FY
authors.lastname: Huang
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Wai-Kay
authors.initials: WK
authors.lastname: Seto
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: James
authors.initials: J
authors.lastname: Fung
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Danny Ka-Ho
authors.initials: DK
authors.lastname: Wong
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Man-Fung
authors.initials: MF
authors.lastname: Yuen
mesh_terms: D000368:Aged; D063646:Carcinogenesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors