Sequential accumulation of the mutations in core promoter of hepatitis B virus is associated with the development of hepatocellular carcinoma in Qidong, China.
OBJECTIVE
To investigate the mutations in hepatitis B virus (HBV) that might be related to hepatocellular carcinoma (HCC) in the high-risk area Qidong, China.


METHODS
DNA sequences of HBV basal core promoter (BCP) and the overlapping X gene were determined in 58 HCC and 71 chronic hepatitis (CH) patients. In addition, a consecutive series of plasma samples from 15 HCC cases were employed to compare the CP/X sequences before and after the occurrence of HCC.


RESULTS
T1762/A1764 double mutation was frequently found in Qidong patients, regardless of clinical status (65.5% in HCC and 73.2% in CH, P>0.05). Unexpectedly, the adjacent T1766/A1768 mutation significantly increased the risk of HCC (P<0.05). Moreover, the prevalence of triple mutations in BCP was significantly higher in patients with HCC than those with CH (P<0.05). The longitudinal study demonstrated that the mutations in BCP were gradually accumulated during the development of HCC. Colony formation assay showed while A1764 mutation alone did not alter the colony-inhibitory activity of HBx, double or triple mutations largely abrogated this effect.


CONCLUSIONS
The complex mutation involving T1766/A1768 was closely related to HCC. The enhanced risk of HCC caused by BCP variants could be attributable partially to the aberrant activity of HBx.
Guo
Xia
X
National Laboratory of Oncogene and Related Genes, Cancer Institute of Shanghai Jiao-Tong University, School of Medicine, Shanghai 200032, China.
Jin
Yan
Y
Qian
Gengsun
G
Tu
Hong
H
D000328:Adult; D019943:Amino Acid Substitution; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000821:virology; D002681:China; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D005814:Genes, Viral; D006515:Hepatitis B virus / Q000235:genetics* / Q000472:pathogenicity*; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000821:virology*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000821:virology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics
D017931:DNA Primers; D004279:DNA, Viral; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein