HOT SPOT MUTATION OF HEPATITIS B VIRUS PRE-S2 GENE RELATED TO HEPATOCELLULAR CARCINOMA IN ASIAN CHILDREN

Abstract

Introduction: The risk factors and their carcinogenesis in childhood hepatocellular carcinoma (HCC) remains poorly understood. Childhood HCC, however, is a real concern as most of them behave aggressively and have a high mortality rate. Purpose: To address these issues, we conducted a retrospective study of childhood HCCs in Asia. Patients and methods: A retrospective study of 42 HCC cases in Asian children from Vietnam, Korea, Taiwan and Japan was conducted. Direct detection of HBV DNA and HCV RNA in tumor tissues and their genomic characterization were performed. Results: HBV DNA in HCC tissues was detected in 36 of 42 (86%) cases tested, while no HCV RNA was detectable in any of HCCs. Twenty of 36 (56%) HCC cases were accompanied by cirrhosis. Surprisingly, very high prevalence of HBV pre-S deletion mutant was recognized in 27 of 30 (90%) HCCs examined. They occurred most frequently in pre-S2 (20/27; 74%) followed by pre-S1 (5/27; 18.5%) and both pre-S1/S2 (2/27, 7.4%). Interestingly, the pre-S2 mutant consistently appeared with deletion at nt 4– 57 in all of the 20 cases with pre-S2 mutant (100%) and within this locus in the two cases with both preS-1/S2 mutant. Type II ground-glass hepatocytes in the nontumorous livers were seen in 15 of the 22 HCCs with pre- S2 deletion mutant (68%). This hot spot mutation in the pre-S2 was further confirmed by complete genomic sequence of HBV in a Japanese boy who eventually developed HCC. Conclusions: HBV is a major contributor to the development of HCC in Asian children. HBV pre-S2 deletion mutant at nt 4–57 which has CD8 T cell epitope, could be responsible for the emergence and aggressive outcome of childhood HCC. Determination of this hot spot mutation in the pre-S2 region could be a useful index for predicting the clinical outcome of HCC development.