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Serum p53 gene polymorphisms and severity of hepatitis B or C-related chronic liver diseases in Taiwan

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Abstract

Background and aims

Polymorphisms of p53 gene are known to play an important role in hepatocarcinogenesis. We aimed to investigate the impact of p53 polymorphisms on disease progression by evaluating their prevalence among chronic hepatitis B (CHB) or hepatitis C (CHC) patients with different stages of liver disease.

Methods

A total of 215 CHB, 108 CHC patients with different stages of liver disease and 49 healthy controls were consecutively enrolled. The codon 249 p53 mutations as well as codon 72 polymorphisms were assayed by molecular methods, and their prevalence among the enrolled subjects was evaluated.

Results

All patients and controls had codon 249 wild-type sequences. Among codon 72 sequences, Pro/Pro allele frequency of Hepatitis B-related HCC (31.4%), cirrhosis (26.9%), HBV carriers (26.3%), hepatitis C-related cirrhosis (39.1%), and CHC patients (24%) were higher than that of healthy controls (18.4%). After adjustment for sex and age, codon 72 mutant and mixed type were associated with a higher likelihood of asymptomatic carrier state than those with wild type in CHB patients [odd ratio (OR): 2.53, 95% confidence interval (CI) 1.06–6.03, P = 0.037]. However, the prevalence of codon 72 mutant and mixed type were comparable with wild type among CHC patients with HCC (OR 0.70, 95% CI 0.28–1.72, P = 0.433).

Conclusions

Although serum 249serine p53 mutation is rarely found in Taiwanese patients, HBV carriers have a higher prevalence of codon 72 mutants than patients with much severe liver diseases or HCV infection, which implies that codon 72 mutants may affect at an earlier stage of HBV infection. Further studies are necessary to delineate the interactions of p53 mutations with HBV infection.

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Abbreviations

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

LC:

Liver cirrhosis

ASC:

Asymptomatic HBV carriers

CPH:

Chronic persistent hepatitis

CAH:

Chronic active hepatitis

HCC:

Hepatocellular carcinoma

References

  1. Kao JH, Chen DS. Changing disease burden of hepatocellular carcinoma in the Far East and Southeast Asia. Liver Int 2005;25:696–703

    Article  PubMed  Google Scholar 

  2. Kao JH. Hepatitis B virus genotypes and hepatocellular carcinoma in Taiwan. Intervirology 2003;46:400–407

    Article  PubMed  Google Scholar 

  3. Poeta ML, Manola J, Goldwasser MA, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 2007;357:2552–2561

    Article  PubMed  CAS  Google Scholar 

  4. Kimbi GC, Kew MC, Yu MC, Arakawa K, Hodkinson J. 249ser p53 mutation in the serum of black southern African patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2005;20:1185–1190

    Article  PubMed  CAS  Google Scholar 

  5. Challen C, Lunec J, Warren W, Collier J, Bassendine MF. Analysis of the p53 tumor-suppressor gene in hepatocellular carcinomas from Britain. Hepatology 1992;16:1362–1366

    Article  PubMed  CAS  Google Scholar 

  6. Coursaget P, Depril N, Chabaud M, et al. High prevalence of mutations at codon 249 of the p53 gene in hepatocellular carcinomas from Senegal. Br J Cancer 1993;67:1395–1397

    Article  PubMed  CAS  Google Scholar 

  7. Zhu ZZ, Cong WM, Liu SF, et al. A p53 polymorphism modifies the risk of hepatocellular carcinoma among non-carriers but not carriers of chronic hepatitis B virus infection. Cancer Lett 2005;229:77–83

    Article  PubMed  CAS  Google Scholar 

  8. Yu MW, Yang SY, Chiu YH, Chiang YC, Liaw YF, Chen CJ. A p53 genetic polymorphism as a modulator of hepatocellular carcinoma risk in relation to chronic liver disease, familial tendency, and cigarette smoking in hepatitis B carriers. Hepatology 1999;29:697–702

    Article  PubMed  CAS  Google Scholar 

  9. Yu MW, Chen CJ. Hepatitis B and C viruses in the development of hepatocellular carcinoma. Crit Rev Oncol Hematol 1994;17:71–91

    Article  PubMed  CAS  Google Scholar 

  10. Foulkes WD. p53—master and commander. N Engl J Med 2007;357:2539–541

    Article  PubMed  CAS  Google Scholar 

  11. Van Dyke T. p53 and tumor suppression. N Engl J Med 2007;356:79–81

    Article  PubMed  Google Scholar 

  12. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000;408:307–310

    Article  PubMed  CAS  Google Scholar 

  13. Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol 2007;8:275–283

    Article  PubMed  CAS  Google Scholar 

  14. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994;54:4855–4878

    PubMed  CAS  Google Scholar 

  15. Montesano R, Hainaut P, Wild CP. Hepatocellular carcinoma: from gene to public health. J Natl Cancer Inst 1997;89:1844–1851

    Article  PubMed  CAS  Google Scholar 

  16. Kirk GD, Camus-Randon AM, Mendy M, et al. Ser-249 p53 mutations in plasma DNA of patients with hepatocellular carcinoma from The Gambia. J Natl Cancer Inst 2000;92:148–153

    Article  PubMed  CAS  Google Scholar 

  17. Ozturk M. p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet 1991;338:1356–59

    Article  PubMed  CAS  Google Scholar 

  18. Aguilar F, Harris CC, Sun T, Hollstein M, Cerutti P. Geographic variation of p53 mutational profile in nonmalignant human liver. Science 1994;264:1317–1319

    Article  PubMed  CAS  Google Scholar 

  19. Ming L, Thorgeirsson SS, Gail MH, et al. Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China. Hepatology 2002;36:1214–1220

    Article  PubMed  CAS  Google Scholar 

  20. Dumont P, Leu JI, Della Pietra AC III, George DL, Murphy M. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 2003;33:357–365

    Article  PubMed  CAS  Google Scholar 

  21. Nawroz H, Koch W, Anker P, Stroun M, Sidransky D. Microsatellite alterations in serum DNA of head and neck cancer patients. Nat Med 1996;2:1035–1037

    Article  PubMed  CAS  Google Scholar 

  22. Aguilar F, Hussain SP, Cerutti P. Aflatoxin B1 induces the transversion of G–>T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci USA 1993;90:8586–8590

    Article  PubMed  CAS  Google Scholar 

  23. Chen XQ, Stroun M, Magnenat JL, et al. Microsatellite alterations in plasma DNA of small cell lung cancer patients. Nat Med 1996;2:1033–1035

    Article  PubMed  CAS  Google Scholar 

  24. Wong IH, Lo YM, Zhang J, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res 1999;59:71–73

    PubMed  CAS  Google Scholar 

  25. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis 2002;2:395–403

    Article  PubMed  Google Scholar 

  26. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225–241

    Article  PubMed  CAS  Google Scholar 

  27. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236

    Article  PubMed  Google Scholar 

  28. Kao JH, Tsai SL, Chen PJ, et al. A clinicopathologic study of chronic non-A, non-B (type C) hepatitis in Taiwan: comparison between posttransfusion and sporadic patients. J Hepatol 1994;21:244–249

    Article  PubMed  CAS  Google Scholar 

  29. Kawajiri K, Nakachi K, Imai K, Watanabe J, Hayashi SI. Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer. Carcinogenesis 1993;4:1085–1089

    Article  Google Scholar 

  30. Harris CC, Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 1993;329:1318–1327

    Article  PubMed  CAS  Google Scholar 

  31. Sheen IS, Jeng KS, Wu JY. Is p53 gene mutation an indicator of the biological behaviors of recurrence of hepatocellular carcinoma? World J Gastroenterol 2003;9:1202–1207

    PubMed  CAS  Google Scholar 

  32. Ding X, Park YN, Taltavull TC, et al. Geographic characterization of hepatitis virus infections, genotyping of hepatitis B virus, and p53 mutation in hepatocellular carcinoma analyzed by in situ detection of viral genomes from carcinoma tissues: comparison among six different countries. Jpn J Infect Dis 2003;56:12–18

    PubMed  CAS  Google Scholar 

  33. Weston A, Pan CF, Ksieski HB, et al. p53 haplotype determination in breast cancer. Cancer Epidemiol Biomarkers Prev 1997;6:105–112

    PubMed  CAS  Google Scholar 

  34. Ross RK, Yuan JM, Yu MC, et al. Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 1992;339:943–946

    Article  PubMed  CAS  Google Scholar 

  35. Wu-Williams AH, Zeise L, Thomas D. Risk assessment for aflatoxin B1: a modeling approach. Risk Anal 1992;12:559–567

    Article  PubMed  CAS  Google Scholar 

  36. Yoon YJ, Chang HY, Han KH, et al. MDM2 and p53 polymorphisms are associated with the development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Carcinogenesis 2008;29:1192–1196

    Article  PubMed  CAS  Google Scholar 

  37. Wang SH, Yeh SH, Lin WH, Wang HY, Chen DS, Chen PJ. Identification of androgen response elements in the enhancer I of hepatitis B virus: A mechanism for sex disparity in chronic hepatitis B. Hepatology 2009;50:1392–1402

    Google Scholar 

  38. Bond GL, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 2004;119:591–602

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank colleagues in the National Taiwan University Hospital, Taipei, Taiwan, who enrolled and followed the patients, and research assistants who assisted in laboratory analyses and collected clinical information. This study was supported by grants from the Lotung St Mary’s Hospital (Project No. 97005), and the Department of Heath, Executive Yuan, Taiwan.

Conflict of interest

Pei-Jer Chen: Consultant for Novartis and Roche. Ding-Shinn Chen: Consultant for Novartis and GlaxoSmithKline. Jia-Horng Kao: Consultant for Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Omrix, Roche, and Schering-Plough; on speaker’s bureau for Roche, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, and Schering-Plough. All other authors have nothing to declare.

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Correspondence to Jia-Horng Kao.

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Mah, YH., Hsu, CS., Liu, CH. et al. Serum p53 gene polymorphisms and severity of hepatitis B or C-related chronic liver diseases in Taiwan. Hepatol Int 5, 814–821 (2011). https://doi.org/10.1007/s12072-010-9248-5

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  • DOI: https://doi.org/10.1007/s12072-010-9248-5

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