Premium
Polymorphisms of the core, NS3, and NS5A proteins of hepatitis C virus genotype 1b associate With development of hepatocellular carcinoma
Author(s) -
ElShamy Ahmed,
Shindo Michiko,
Shoji Ikuo,
Deng Lin,
Okuno Tadao,
Hotta Hak
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26205
Subject(s) - ns5a , ns3 , hepatocellular carcinoma , hepatitis c virus , ribavirin , medicine , virology , genotype , hepacivirus , hepatitis c , gastroenterology , virus , biology , gene , genetics
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. Conclusion : 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 ). (H EPATOLOGY 2013;58:555‐563)