The characteristic changes in hepatitis B virus x region for hepatocellular carcinoma: a comprehensive analysis based on global data

• Published in: PloS one Vol. 10; no. 5; p. e0125555
• Main Authors: Li, Wenwen, Goto, Kaku, Matsubara, Yasuo, Ito, Sayaka, Muroyama, Ryosuke, Li, Qiang, Kato, Naoya
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05-05-2015; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Analysis; Antigens; Apoptosis; Binding sites; Carcinoma, Hepatocellular - epidemiology; Carcinoma, Hepatocellular - etiology; Cell Transformation, Viral; Child; Child, Preschool; Computational Biology; Databases, Nucleic Acid; Deoxyribonucleic acid; DNA; Epitopes; Female; Gene mutation; Genetic aspects; Genomes; Genotype; Genotype & phenotype; Genotypes; Global Health; Health aspects; Hepatitis; Hepatitis B; Hepatitis B - complications; Hepatitis B - virology; Hepatitis B virus; Hepatitis B virus - genetics; Hepatocellular carcinoma; Humans; Infections; Liver cancer; Liver diseases; Liver Neoplasms - epidemiology; Liver Neoplasms - etiology; Male; Medicine; Middle Aged; miRNA; Mutation; Patients; Phases; Proteins; Regression analysis; Risk; Risk analysis; Risk factors; Science; Trans-Activators - chemistry; Trans-Activators - genetics; Viruses; Young Adult; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0125555

Mutations in hepatitis B virus (HBV) X region (HBx) play important roles in hepatocarcinogenesis while the results remain controversial. We sought to clarify potential hepatocellular carcinoma (HCC)-characteristic mutations in HBx from HBV genotype C-infected patients and the distribution of those mutations in different disease phases and genotypes.
HBx sequences downloaded from an online global HBV database were screened and then classified into Non-HCC or HCC group by diagnosis information. Patients' data of patient age, gender, country or area, and viral genotype were also extracted. Logistic regression was performed to evaluate the effects of mutations on HCC risk.
1) Full length HBx sequences (HCC: 161; Non-HCC: 954) originated from 1115 human sera across 29 countries/areas were extracted from the downloaded 5956 HBx sequences. Genotype C occupied 40.6% of Non-HCC (387/954) and 89.4% of HCC (144/161). 2) Sixteen nucleotide positions showed significantly different distributions between genotype C HCC and Non-HCC groups. 3) Logistic regression showed that mutations A1383C (OR: 2.32, 95% CI: 1.34-4.01), R1479C/T (OR: 1.96, 95% CI: 1.05-3.64; OR: 5.15, 95% CI: 2.53-10.48), C1485T (OR: 2.40, 95% CI: 1.41-4.08), C1631T (OR: 4.09, 95% CI: 1.41-11.85), C1653T (OR: 2.58, 95% CI: 1.59-4.19), G1719T (OR: 2.11, 95% CI: 1.19-3.73), and T1800C (OR: 23.59, 95% CI: 2.25-247.65) were independent risk factors for genotype C HBV-related HCC, presenting different trends among individual disease phases. 4) Several genotype C HCC risk mutations pre-existed, even as major types, in early disease phases with other genotypes.
Mutations associated with HCC risk were mainly located in HBx transactivation domain, viral promoter, protein/miRNA binding sites, and the area for immune epitopes. Furthermore, the signatures of these mutations were unique to disease phases leading to HCC, suggesting molecular counteractions between the virus and host during hepatocarcinogenesis.