Impact of Hepatitis B Virus (HBV) X Gene Mutations on Hepatocellular Carcinoma Development in Chronic HBV Infection

June 3, 2011

Clinical and Vaccine Immunology, June 2011,p. 914-921, Vol. 18, No. 6

1556-6811/11/$12.00+0 doi:10.1128/CVI.00474-10

Microbial Immunology

Impact of Hepatitis B Virus (HBV) X Gene Mutations on Hepatocellular Carcinoma

Development in Chronic HBV Infection

Jong-Han Lee1, Kwang-Hyub Han2, Jae Myun Lee3, Jeon Han Park3,* and Hyon-Suk

Kim1,*

1Department of Laboratory Medicine, Yonsei University College of Medicine,

Seoul, Korea 2Department of Internal Medicine, Yonsei University College of

Medicine, Seoul, Korea 3Department of Microbiology, Yonsei University College of

Medicine, Seoul, Korea

Received 1 November 2010/ Returned for modification 16 December 2010/ Accepted

31 March 2011

ABSTRACT

The hepatitis B virus (HBV) PreS mutations C1653T, T1753V, and A1762T/G1764A

were reported as a strong risk factor of hepatocellular carcinoma (HCC) in a

meta-analysis. HBV core promoter overlaps partially with HBx coding sequence, so

the nucleotide 1762 and 1764 mutations induce HBV X protein (HBx) 130 and 131

substitutions. We sought to elucidate the impact of HBx mutations on HCC

development. Chronically HBV-infected patients were enrolled in this study: 42

chronic hepatitis B (CHB) patients, 23 liver cirrhosis (LC) patients, and 31 HCC

patients. Direct sequencing showed HBx131, HBx130, HBx5, HBx94, and HBx38 amino

acid mutations were common in HCC patients. Of various mutations, HBx130+HBx131

(double) mutations and HBx5+HBx130+HBx131 (triple) mutations were significantly

high in HCC patients. Double and triple mutations increased the risk for HCC by

3.75-fold (95% confidence interval [CI] = 1.101 to 12.768, P = 0.033) and

5.34-fold (95% CI = 1.65 to 17.309, P = 0.005), respectively, when HCC patients

were compared to CHB patients. Functionally, there were significantly higher

levels of NF-B activity in cells with the HBx5 mutant and with the double

mutants than that of wild-type cells and the triple-mutant cells. The triple

mutation did not increase NF-B activity. Other regulatory pathways seem to exist

for NF-B activation. In conclusion, a specific HBx mutation may contribute to

HCC development by activating NF-B activity. The HBx5 mutation in genotype C2

HBV appears to be a risk factor for the development of HCC and may be used to

predict the clinical outcomes of patients with chronic HBV infection.

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* Corresponding author. Mailing address for H.-S. Kim: Department of Laboratory

Medicine, Yonsei University College of Medicine, 250 Seongsan-no, Seodaemun-gu,

Seoul 120-752, Korea. Phone: 82 2 2228 2443. Fax: 82 2 364 1583. E-mail:

kimhs54@.... Mailing address for J. H. Park: Department of Microbiology,

Yonsei University College of Medicine, 250 Seongsan-no, Seodaemun-gu, Seoul

120-752, Korea. Phone: 82 2 2228 1815. Fax: 82 2 392 7088. E-mail:

jhpark5277@....

June 3, 2011