title: Progressive accumulation of mutations in the hepatitis B virus genome and its impact on time to diagnosis of hepatocellular carcinoma.
abstract: To evaluate how hepatitis B virus (HBV) genetic variation affected progression from chronic carrier state to hepatocellular carcinoma (HCC), we analyzed HBV full-length sequences in blood obtained <1-20 years before diagnosis from 117 HCC cases and 118 controls nested in a cohort of 4,841 HBV carriers, for whom HBV genotypes B and C are predominant. The relationship between each viral single-nucleotide polymorphism (SNP) and HCC development was assessed using ordinal logistic models according to five periods of time to diagnosis (TTD). Thirty-one HBV-SNPs showed significant association with TTD after adjustment for HBV genotype, 24 of which could also be analyzed with an extended analysis on the full-length data in conjunction with 512 partial sequences (nucleotides 2,436-1,623) from the cohort. The obtained 10 robust candidate HBV-SNPs (P ≤ 0.0304), which showed odds ratios ranging from 1.89 to 8.68, were further confirmed in 163 GenBank HBV-HCC sequences from nine Asia regions, assayed after HCC diagnosis, representing the end stage of progressive hepatic diseases. The prevalence of these HBV-SNPs and their cumulative number, presented in terms of mutation score, increased with time approaching HCC diagnosis, with an odds ratio of 2.17, 4.21, 8.15, and 19.15, respectively, for the mutation score of 1, 2, 3, and ≥4 versus 0. The mutation score for predicting short-term HCC risk outperformed other factors, including HBV-DNA levels, viral genotype, and various combinations of risk factors, and revealed increasing accuracy with shorter TTD (<4.5 years before diagnosis: area under the curve = 0.83-0.89; sensitivity = 72.7%-94.1%; specificity = 58.3%-70.5%; conditioned on optimized cutoff for genotype B and C, respectively).
  
  
  
  Identifying and tracking viral mutations is important for monitoring hepatitis B progression and early detection of HCC. (Hepatology 2016;64:720-731).
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Feng-Yu
authors.initials: FY
authors.lastname: Sung
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Lan
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Chi-Jung
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan.
authors.forename: Chih-Lin
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Lin
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Whei
authors.initials: MW
authors.lastname: Yu
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000821:virology*; D016022:Case-Control Studies; D015331:Cohort Studies; D016679:Genome, Viral; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000067552:Mutation Accumulation