Fine mapping of hepatitis B virus pre-S deletion and its association with hepatocellular carcinoma.
BACKGROUND
Naturally occurring pre-S deletion mutants have been identified in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).


OBJECTIVE
This study investigated whether specific deletions within the pre-S region were associated with HCC development.


METHODS
The virologic characteristics of 56 HBV chronic carriers and 112 age-matched patients with HBV-related HCC were examined.


RESULTS
The HCC patients had a significantly higher frequency of high viral load, basal core promoter mutation and pre-S deletion than chronic carriers. Sequencing analysis showed that the deleted regions were clustered mainly in the C terminus of pre-S1 (70.5%) and the N terminus of pre-S2 (72.7%) in HCC patients. Immuno-epitope mapping of these pre-S deletion sequences showed that all the deletion regions encompassed T- and B- cell epitopes and the B-cell epitope at amino acid 1-6 of pre-S2 was significantly deleted in HCC patients (60.0% vs. 0.0%; P = 0.036). Functional mapping of these deletion mutants showed that most of HCC patients lost one or more functional sites and the deletion of site for viral secretion (aa 1-5 of pre-S2 domain) was significantly detected in HCC patients than chronic carriers (62.5% vs. 0.0%; P = 0.029). Computational protein function prediction indicated that these mutants may have different molecular functions and participate in other biological processes compared with wild-type pre-S.


CONCLUSIONS
Deletion of B-cell epitope at amino acid 1-6 of pre-S2 region and the site for virion secretion are significantly associated with the development of HCC in HBV carriers.
Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Jia-Horng
JH
Kao
Chun-Jen
CJ
Liu
Guey-Mei
GM
Jow
Pei-Jer
PJ
Chen
Ding-Shinn
DS
Chen
Bing-Fang
BF
Chen
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology*; D002353:Carrier State; D004279:DNA, Viral / Q000032:analysis; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D005814:Genes, Viral / Q000235:genetics*; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics* / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000473:pathology / Q000821:virology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020161:Physical Chromosome Mapping
D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D000410:Alanine Transaminase