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J. Virol. doi:10.1128/JVI.01197-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Genotype-Specific Genomic Markers Associated with Primary Hepatoma Based on Complete Genomic Sequencing of Hepatitis B Virus

Institute of Digestive Disease and Department of Medicine and Therapeutics, Department of Biochemistry, Department of Computer Science & Engineering, Department of Clinical Oncology, The Chinese University of Hong Kong, Victorian Infectious Diseases Research Laboratory, Melbourne, Australia

^* To whom correspondence should be addressed. Email: hlychan{at}cuhk.edu.hk.

	Abstract

We aimed to identify genomic markers in HBV that are associated with HCC development by comparing the complete genomic sequence of HBV among patients with HCC and those without. 100 patients with HBV-related HCC and 100 age-matched HBV-infected non-HCC patients (control) were studied. HBV DNA from serum was directly sequenced to study the whole viral genome. Data mining and rule learning was employed to develop diagnostic algorithms. An independent cohort of 132 cases (43 HCC and 89 non-HCC) was used to validate the accuracy of these algorithms. Among the 100 cases of HCC, 37 had genotype B (all subgenotype Ba) and 63 cases had genotype C (16 subgenotype Ce and 47 subgenotype Cs) HBV infection. In the control group, 51 had genotype B and 49 genotype C (10 subgenotype Ce and 39 subgenotype Cs) HBV infection. Genomic algorithms associated with HCC were derived based on genotype/subgenotype specific mutations. In genotype B HBV, mutations C1165T, A1762T and G1764A, T2712C/A/G, and A/T2525C were associated with HCC. HCC-related mutations T31C, T53C and A1499G were associated with HBV subgenotype Ce and mutations G1613A, G1899A, T2170C/G, T2441C were associated with HBV subgenotype Cs. Amino acid changes caused by these mutations were found in the X, envelope and precore/core regions in association with HBV genotype B, Ce and Cs, respectively. In conclusion, infection by different genotypes of HBV (B, Ce, Cs) carries different genomic markers for HCC at different parts of the HBV genome. Different HBV genotypes may have different virologic mechanisms of hepatocarcinogenesis.