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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Division of advanced genome medicine, Advanced clinical research center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Wenwen
W
Li
Division of advanced genome medicine, Advanced clinical research center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kaku
K
Goto
Division of advanced genome medicine, Advanced clinical research center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yasuo
Y
Matsubara
Division of advanced genome medicine, Advanced clinical research center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Sayaka
S
Ito
Division of advanced genome medicine, Advanced clinical research center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Ryosuke
R
Muroyama
Affiliated Infectious Disease Hospital of Shandong University, Jinan, Shandong, China.
Qiang
Q
Li
Division of advanced genome medicine, Advanced clinical research center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Naoya
N
Kato
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000209:etiology*; D002472:Cell Transformation, Viral; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D030561:Databases, Nucleic Acid; D005260:Female; D005838:Genotype; D014943:Global Health; D006509:Hepatitis B / Q000150:complications* / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012306:Risk; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins; D055815:Young Adult
D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein