{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T15:46:47Z","timestamp":1759160807412,"version":"3.27.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:p>To evaluate how hepatitis B virus (HBV) genetic variation affected progression from chronic carrier state to hepatocellular carcinoma (HCC), we analyzed HBV full\u2010length sequences in blood obtained &lt;1\u201020 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\u2010nucleotide polymorphism (SNP) and HCC development was assessed using ordinal logistic models according to five periods of time to diagnosis (TTD). Thirty\u2010one HBV\u2010SNPs showed significant association with TTD after adjustment for HBV genotype, 24 of which could also be analyzed with an extended analysis on the full\u2010length data in conjunction with 512 partial sequences (nucleotides 2,436\u20101,623) from the cohort. The obtained 10 robust candidate HBV\u2010SNPs (<jats:italic toggle=\"yes\">P<\/jats:italic> \u2264 0.0304), which showed odds ratios ranging from 1.89 to 8.68, were further confirmed in 163 GenBank HBV\u2010HCC sequences from nine Asia regions, assayed after HCC diagnosis, representing the end stage of progressive hepatic diseases. The prevalence of these HBV\u2010SNPs 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 \u22654 versus 0. The mutation score for predicting short\u2010term HCC risk outperformed other factors, including HBV\u2010DNA levels, viral genotype, and various combinations of risk factors, and revealed increasing accuracy with shorter TTD (&lt;4.5 years before diagnosis: area under the curve = 0.83\u20100.89; sensitivity = 72.7%\u201094.1%; specificity = 58.3%\u201070.5%; conditioned on optimized cutoff for genotype B and C, respectively). <jats:italic toggle=\"yes\">Conclusions:<\/jats:italic> Identifying and tracking viral mutations is important for monitoring hepatitis B progression and early detection of HCC. (H<jats:sc>epatology<\/jats:sc> 2016;64:720\u2010731)<\/jats:p>","DOI":"10.1002\/hep.28654","type":"journal-article","created":{"date-parts":[[2016,5,26]],"date-time":"2016-05-26T23:58:07Z","timestamp":1464307087000},"page":"720-731","update-policy":"http:\/\/dx.doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":12,"title":["Progressive accumulation of mutations in the hepatitis B virus genome and its impact on time to diagnosis of hepatocellular carcinoma"],"prefix":"10.1097","volume":"64","author":[{"given":"Feng\u2010Yu","family":"Sung","sequence":"first","affiliation":[{"name":"Institute of Epidemiology and Preventive Medicine, College of Public Health,National Taiwan University,Taipei,Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia\u2010Ying","family":"Lan","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology and Preventive Medicine, College of Public Health,National Taiwan University,Taipei,Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi\u2010Jung","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology and Preventive Medicine, College of Public Health,National Taiwan University,Taipei,Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chih\u2010Lin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Ren\u2010Ai Branch,Taipei City Hospital,Taipei,Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun\u2010Jen","family":"Liu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei\u2010Jer","family":"Chen","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi\u2010Ming","family":"Lin","sequence":"additional","affiliation":[{"name":"Liver Research Unit, Chang Gung Memorial Hospital,Chang Gung University College of Medicine,Taoyuan,Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming\u2010Whei","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology and Preventive Medicine, College of Public Health,National Taiwan 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