Advertisement

Archives of Virology

, Volume 153, Issue 10, pp 1807–1812 | Cite as

High prevalence of hepatitis B virus pre-S mutation and its association with hepatocellular carcinoma in Qidong, China

  • Zhigang Cao
  • Xin Bai
  • Xia Guo
  • Yan Jin
  • Gengsun Qian
  • Hong Tu
Original Article

Abstract

We investigated the frequency and the clinical relevance of hepatitis B virus (HBV) pre-S mutations in Qidong, China. The results showed HBV pre-S mutants were detected in 48.4% (47/97) of patients with HBV infection. Both pre-S deletion and pre-S2 start codon mutations were more frequently found in HCC than in CH patients (51.1% vs. 18.0%, P < 0.01 and 21.2% vs. 8.0%, P = 0.06). In most cases, pre-S mutants coexisted with the wild-type HBV strain. Longitudinal observation clearly revealed that in four of five cases, HBV deletion mutants emerged during the course of HBV infection and eventually became the predominant or exclusive viral population at the stage of HCC. Thus, it was concluded that HBV pre-S mutations were highly prevalent and closely related to HCC in Qidong. Our results also provided direct evidence that pre-S deletion mutants were not acquired from the beginning of infection but arose de novo during the progression of liver disease.

Keywords

Viral Population Basal Core Promoter Qidong Area 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by grant 30471951 from the National Natural Science Foundation of China and grant 80-1 from the National Laboratory of Oncogenes and Related Genes. The authors thank Dr. John Groopman, Thomas Kensler and Jinbing Wang for their contributions to the prospective cohort in Qidong.

References

  1. 1.
    Baumert TF, Barth H, Blum HE (2005) Genetic variants of hepatitis B virus and their clinical relevance. Minerva Gastroenterol Dietol 51:95–108PubMedGoogle Scholar
  2. 2.
    Buti M, Rodriguez-Frias F, Jardi R, Esteban R (2005) Hepatitis B virus genome variability and disease progression: the impact of pre-core mutants and HBV genotypes. J Clin Virol 34(Suppl 1):S79–S82PubMedCrossRefGoogle Scholar
  3. 3.
    Chai N, Gudima S, Chang J, Taylor J (2007) Immunoadhesins containing pre-S domains of hepatitis B virus large envelope protein are secreted and inhibit virus infection. J Virol 81:4912–4918PubMedCrossRefGoogle Scholar
  4. 4.
    Chen BF, Liu CJ, Jow GM, Chen PJ, Kao JH, Chen DS (2006) High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. Gastroenterology 130:1153–1168PubMedCrossRefGoogle Scholar
  5. 5.
    Chen CH, Hung CH, Lee CM, Hu TH, Wang JH, Wang JC, Lu SN, Changchien CS (2007) Pre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patients. Gastroenterology 133:1466–1474PubMedCrossRefGoogle Scholar
  6. 6.
    Chen JG, Zhu J, Parkin DM, Zhang YH, Lu JH, Zhu YR, Chen TY (2006) Trends in the incidence of cancer in Qidong, China, 1978–2002. Int J Cancer 119:1447–1454PubMedCrossRefGoogle Scholar
  7. 7.
    Chen JG, Kuang SY, Egner PA, Lu JH, Zhu YR, Wang JB, Zhang BC, Chen TY, Munoz A, Kensler TW, Groopman JD (2007) Acceleration to death from liver cancer in people with hepatitis B viral mutations detected in plasma by mass spectrometry. Cancer Epidemiol Biomarkers Prev 16:1213–1218PubMedCrossRefGoogle Scholar
  8. 8.
    Chinese Society of Hepatology, Chinese Medical Association and Chinese Society of Infectious Diseases, Chinese Medical Association (2007) Guideline on prevention and treatment of chronic hepatitis. Chin Med J 120:2159–2173Google Scholar
  9. 9.
    Chisari FV, Ferrari C (1995) Hepatitis B virus immunopathogenesis. Annu Rev Immunol 13:29–60PubMedCrossRefGoogle Scholar
  10. 10.
    Choi MS, Kim DY, Lee DH, Lee JH, Koh KC, Paik SW, Rhee JC, Yoo BC (2007) Clinical significance of pre-S mutations in patients with genotype C hepatitis B virus infection. J Viral Hepat 14:161–168PubMedCrossRefGoogle Scholar
  11. 11.
    Fan YF, Lu CC, Chen WC, Yao WJ, Wang HC, Chang TT, Lei HY, Shiau AL, Su IJ (2001) Prevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infection. Hepatology 33:277–286PubMedCrossRefGoogle Scholar
  12. 12.
    Fernholz D, Stemler M, Brunetto M, Bonino F, Will H (1991) Replicating and virion secreting hepatitis B mutant virus unable to produce preS2 protein. J Hepatol 13(Suppl 4):S102–S104PubMedCrossRefGoogle Scholar
  13. 13.
    Fernholz D, Galle PR, Stemler M, Brunetto M, Bonino F, Will H (1993) Infectious hepatitis B virus variant defective in pre-S2 protein expression in a chronic carrier. Virology 194:137–148PubMedCrossRefGoogle Scholar
  14. 14.
    Gao ZY, Li T, Wang J, Du JM, Li YJ, Li J, Lu FM, Zhuang H (2007) Mutations in preS genes of genotype C hepatitis B virus in patients with chronic hepatitis B and hepatocellular carcinoma. J Gastroenterol 42:761–768PubMedCrossRefGoogle Scholar
  15. 15.
    Guo X, Jin Y, Qian G, Xu L, Tu H (2007) Full-geneome sequence analysis of hepatitis B virus isolated from hepatocellular carcinoma in high incidence area Qidong. Tumor in Chinese with English abstract 27:4Google Scholar
  16. 16.
    Hartmann-Stuhler C, Prange R (2001) Hepatitis B virus large envelope protein interacts with gamma2-adaptin, a clathrin adaptor-related protein. J Virol 75:5343–5351PubMedCrossRefGoogle Scholar
  17. 17.
    Hsieh YH, Su IJ, Wang HC, Chang WW, Lei HY, Lai MD, Chang WT, Huang W (2004) Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis 25:2023–2032PubMedCrossRefGoogle Scholar
  18. 18.
    Hung JH, Su IJ, Lei HY, Wang HC, Lin WC, Chang WT, Huang W, Chang WC, Chang YS, Chen CC, Lai MD (2004) Endoplasmic reticulum stress stimulates the expression of cyclooxygenase–2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase. J Biol Chem 279:46384–46392PubMedCrossRefGoogle Scholar
  19. 19.
    Huy TT, Ushijima H, Win KM, Luengrojanakul P, Shrestha PK, Zhong ZH, Smirnov AV, Taltavull TC, Sata T, Abe K (2003) High prevalence of hepatitis B virus pre-s mutant in countries where it is endemic and its relationship with genotype and chronicity. J Clin Microbiol 41:5449–5455PubMedCrossRefGoogle Scholar
  20. 20.
    Klingmuller U, Schaller H (1993) Hepadnavirus infection requires interaction between the viral pre-S domain and a specific hepatocellular receptor. J Virol 67:7414–7422PubMedGoogle Scholar
  21. 21.
    Kuang SY, Jackson PE, Wang JB, Lu PX, Munoz A, Qian GS, Kensler TW, Groopman JD (2004) Specific mutations of hepatitis B virus in plasma predict liver cancer development. Proc Natl Acad Sci U S A 101:3575–3580PubMedCrossRefGoogle Scholar
  22. 22.
    Lin CL, Liu CH, Chen W, Huang WL, Chen PJ, Lai MY, Chen DS, Kao JH (2007) Association of pre-S deletion mutant of hepatitis B virus with risk of hepatocellular carcinoma. J Gastroenterol Hepatol 22:1098–1103PubMedCrossRefGoogle Scholar
  23. 23.
    Milich DR, McNamara MK, McLachlan A, Thornton GB, Chisari FV (1985) Distinct H-2-linked regulation of T-cell responses to the pre-S and S regions of the same hepatitis B surface antigen polypeptide allows circumvention of nonresponsiveness to the S region. Proc Natl Acad Sci U S A 82:8168–8172PubMedCrossRefGoogle Scholar
  24. 24.
    Milich DR, Thornton GB, Neurath AR, Kent SB, Michel ML, Tiollais P, Chisari FV (1985) Enhanced immunogenicity of the pre-S region of hepatitis B surface antigen. Science 228:1195–1199PubMedCrossRefGoogle Scholar
  25. 25.
    Ming L, Thorgeirsson SS, Gail MH, Lu P, Harris CC, Wang N, Shao Y, Wu Z, Liu G, Wang X, Sun Z (2002) Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China. Hepatology 36:1214–1220PubMedCrossRefGoogle Scholar
  26. 26.
    Pawlotsky JM (2005) The concept of hepatitis B virus mutant escape. J Clin Virol 34(Suppl 1):S125–S129PubMedCrossRefGoogle Scholar
  27. 27.
    Pollicino T, Zanetti AR, Cacciola I, Petit MA, Smedile A, Campo S, Sagliocca L, Pasquali M, Tanzi E, Longo G, Raimondo G (1997) Pre-S2 defective hepatitis B virus infection in patients with fulminant hepatitis. Hepatology 26:495–499PubMedCrossRefGoogle Scholar
  28. 28.
    Pujol FH, Devesa M (2005) Genotypic variability of hepatitis viruses associated with chronic infection and the development of hepatocellular carcinoma. J Clin Gastroenterol 39:611–618PubMedCrossRefGoogle Scholar
  29. 29.
    Raimondo G, Costantino L, Caccamo G, Pollicino T, Squadrito G, Cacciola I, Brancatelli S (2004) Non-sequencing molecular approaches to identify preS2-defective hepatitis B virus variants proved to be associated with severe liver diseases. J Hepatol 40:515–519PubMedCrossRefGoogle Scholar
  30. 30.
    Santantonio T, Jung MC, Schneider R, Fernholz D, Milella M, Monno L, Pastore G, Pape GR, Will H (1992) Hepatitis B virus genomes that cannot synthesize pre-S2 proteins occur frequently and as dominant virus populations in chronic carriers in Italy. Virology 188:948–952PubMedCrossRefGoogle Scholar
  31. 31.
    Seifer M, Heermann KH, Gerlich WH (1990) Expression pattern of the hepatitis B virus genome in transfected mouse fibroblasts. Virology 179:287–299PubMedCrossRefGoogle Scholar
  32. 32.
    Sun Z, Lu P, Gail MH, Pee D, Zhang Q, Ming L, Wang J, Wu Y, Liu G, Zhu Y (1999) Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 30:379–383PubMedCrossRefGoogle Scholar
  33. 33.
    Sun Z, Ming L, Zhu X, Lu J (2002) Prevention and control of hepatitis B in China. J Med Virol 67:447–450PubMedCrossRefGoogle Scholar
  34. 34.
    Suwannakarn K, Tangkijvanich P, Thawornsuk N, Theamboonlers A, Tharmaphornpilas P, Yoocharoen P, Chongsrisawat V, Poovorawan Y (2008) Molecular epidemiological study of hepatitis B virus in Thailand based on the analysis of pre-S and S genes. Hepatol Res 38:244–251PubMedCrossRefGoogle Scholar
  35. 35.
    Tiollais P, Pourcel C, Dejean A (1985) The hepatitis B virus. Nature 317:489–495PubMedCrossRefGoogle Scholar
  36. 36.
    Tong S (2005) Mechanism of HBV genome variability and replication of HBV mutants. J Clin Virol 34(Suppl 1):134–138CrossRefGoogle Scholar
  37. 37.
    Wang HC, Wu HC, Chen CF, Fausto N, Lei HY, Su IJ (2003) Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol 163:2441–2449PubMedGoogle Scholar
  38. 38.
    Wang HC, Chang WT, Chang WW, Wu HC, Huang W, Lei HY, Lai MD, Fausto N, Su IJ (2005) Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes. Hepatology 41:761–770PubMedCrossRefGoogle Scholar
  39. 39.
    Yang L, Parkin DM, Li LD, Chen YD, Bray F (2004) Estimation and projection of the national profile of cancer mortality in China: 1991–2005. Br J Cancer 90:2157–2166PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Zhigang Cao
    • 1
  • Xin Bai
    • 1
  • Xia Guo
    • 1
  • Yan Jin
    • 1
  • Gengsun Qian
    • 1
  • Hong Tu
    • 1
  1. 1.National Laboratory of Oncogene and Related GenesCancer Institute of Shanghai Jiao-Tong UniversityShanghaiPeople’s Republic of China

Personalised recommendations