Association of hepatitis B virus pre-S deletions with the development of hepatocellular carcinoma in Qidong, China.
OBJECTIVE
To investigate the roles of mutations in pre-S and S regions of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China.


METHODS
We conducted an age matched case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence in pre-S/S regions was successfully determined in 96 HCC cases and 97 control subjects. In addition, a consecutive series of samples from 11 HCC cases were employed to evaluate the pre-S deletion patterns before and after the occurrence of HCC.


RESULTS
After adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positivity, pre-S deletions, pre-S2 start codon mutations, and T53C mutation were significantly associated with HCC, showing adjusted odds ratios (ORs) from 1.914 to 3.199. HCC patients also had a lower frequency of T31C mutation in pre-S2 gene, compared with control subjects (0.524; 95% CI 0.280-0.982). HBV pre-S deletions were clustered mainly in the 5' end of pre-S2 region. Multivariate analysis showed that pre-S deletions and pre-S2 start codon mutations were independent risk factors for HCC. The OR (95% CI) were 2.434 (1.063-5.573) and 3.065 (1.099-8.547), respectively. The longitudinal observation indicated that the pre-S deletion mutations were not acquired at the beginning of HBV infection, but that the mutations occurred during the long course of liver disease.


CONCLUSIONS
Pre-S deletions and pre-S2 start codon mutations were independently associated with the development of HCC. The results also provided direct evidence that pre-S deletion mutations were not acquired from the beginning of infection but arose de novo during the progression of liver disease.
Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu Province, China.
Li-Shuai
LS
Qu
Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu Province, China.
Jin-Xia
JX
Liu
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
Tao-Tao
TT
Liu
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
Xi-Zhong
XZ
Shen
Qidong Liver Cancer Institute, Qidong, Jiangsu Province, China.
Tao-Yang
TY
Chen
Qidong Liver Cancer Institute, Qidong, Jiangsu Province, China.
Zheng-Pin
ZP
Ni
Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu Province, China.
Cui-Hua
CH
Lu
D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology*; D016022:Case-Control Studies; D002681:China; D018387:Codon, Initiator; D015331:Cohort Studies; D018450:Disease Progression; D017353:Gene Deletion; D005838:Genotype; D006509:Hepatitis B / Q000150:complications / Q000821:virology*; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D017384:Sequence Deletion; D012907:Smoking
D018387:Codon, Initiator; D006514:Hepatitis B Surface Antigens