Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Virology, Suez Canal University Faculty of Veterinary Medicine, Ismalia, Egypt.
Hepatocellular carcinoma (HCC) is one of the common sequels 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 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 111247) and 6 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) 50 and α-fetoprotein (AFP) levels (>20 ng/L) as independent factors associated with HCC. Kaplan-Meier analysis revealed higher cumulative incidence of HCC for patients infected with HCV isolates with core-Gln(70) , NS3-Tyr(1082) /Gln(1112) 52 or both than for those with Non-(Gln(70) plus NS3-Tyr(1082) /Gln(1112) 53 ). 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, the present results suggest that HCV isolates with core-Gln(70) and/or NS3-Tyr(1082) /Gln(1112) 56 are more closely associated with HCC development compared to those with Non-(Gln(70) plus NS3-Tyr(1082) /Gln(1112) 57 ).