title: Polymorphisms of the core, NS3, and NS5A proteins of hepatitis C virus genotype 1b associate with development of hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the common sequelae of hepatitis C virus (HCV) infection. It remains controversial, however, whether HCV itself plays a direct role in the development of HCC. Although HCV core, NS3, and NS5A proteins were reported to display tumorigenic activities in cell culture and experimental animal systems, their clinical impact on HCC development in humans is still unclear. In this study we investigated sequence polymorphisms in the core protein, NS3, and NS5A of HCV genotype 1b (HCV-1b) in 49 patients who later developed HCC during a follow-up of an average of 6.5 years and in 100 patients who did not develop HCC after a 15-year follow-up. Sequence analysis revealed that Gln at position 70 of the core protein (core-Gln(70) ), Tyr at position 1082 plus Gln at 1112 of NS3 (NS3-Tyr(1082) /Gln(1112) ), and six or more mutations in the interferon/ribavirin resistance-determining region of NS5A (NS5A-IRRDR≥6) were significantly associated with development of HCC. Multivariate analysis identified core-Gln(70) , NS3-Tyr(1082) /Gln(1112) , and α-fetoprotein (AFP) levels (>20 ng/L) as independent factors associated with HCC. Kaplan-Meier analysis revealed a higher cumulative incidence of HCC for patients infected with HCV isolates with core-Gln(70) , NS3-Tyr(1082) /Gln(1112) or both than for those with non-(Gln(70) plus NS3-Tyr(1082) /Gln(1112) ). In most cases, neither the residues at position 70 of the core protein nor positions 1082 and 1112 of the NS3 protein changed during the observation period.
  
  
  CONCLUSIONS
  HCV isolates with core-Gln(70) and/or NS3-Tyr(1082) /Gln(1112) are more closely associated with HCC development compared to those with non-(Gln(70) plus NS3-Tyr(1082) /Gln(1112) ).
authors.affiliation: Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Shamy
authors.forename: Michiko
authors.initials: M
authors.lastname: Shindo
authors.forename: Ikuo
authors.initials: I
authors.lastname: Shoji
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.forename: Tadao
authors.initials: T
authors.lastname: Okuno
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
mesh_terms: D000595:Amino Acid Sequence; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000821:virology*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000821:virology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000453:epidemiology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014758:Viral Core Proteins / Q000032:analysis / Q000235:genetics*; D017361:Viral Nonstructural Proteins / Q000032:analysis / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C069130:nucleocapsid protein, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase