Polymorphisms of the core, NS3, and NS5A proteins of hepatitis C virus genotype 1b associate With development of hepatocellular carcinoma

Authors

  • Ahmed El-Shamy,

    1. Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
    2. Department of Virology, Suez Canal University Faculty of Veterinary Medicine, Ismalia, Egypt
    Current affiliation:
    1. Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York, USA
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    • These authors contributed equally to this work.

  • Michiko Shindo,

    1. Department of Gastroenterology, Akashi City Hospital, Akashi, Japan
    Current affiliation:
    1. Okuno Gastroenterology Clinic, Akashi, Hyogo, Japan
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    • These authors contributed equally to this work.

  • Ikuo Shoji,

    1. Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
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  • Lin Deng,

    1. Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
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  • Tadao Okuno,

    1. Department of Gastroenterology, Akashi City Hospital, Akashi, Japan
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  • Hak Hotta

    Corresponding author
    1. Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
    • Address reprint requests to: Hak Hotta, M.D., Ph.D., Division of Microbiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: hotta@kobe-u.ac.jp fax: +81-78-382-5519

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  • Potential conflict of interest: Nothing to report.

  • Supported in part by Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare, Japan, and a SATREPS Grant from Japan Science and Technology Agency (JST) and Japan International Cooperation Agency (JICA). This study was also carried out as part of Japan Initiative for Global Research Network on Infectious Diseases (J-GRID), Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Global Center of Excellence (G-COE) Program at Kobe University Graduate School of Medicine.

  • See Editorial on Page 491

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-Gln70), Tyr at position 1082 plus Gln at 1112 of NS3 (NS3-Tyr1082/Gln1112), 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-Gln70, NS3-Tyr1082/Gln1112, 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-Gln70, NS3-Tyr1082/Gln1112 or both than for those with non-(Gln70 plus NS3-Tyr1082/Gln1112). 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-Gln70 and/or NS3-Tyr1082/Gln1112 are more closely associated with HCC development compared to those with non-(Gln70 plus NS3-Tyr1082/Gln1112). (HEPATOLOGY 2013;58:555-563)

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