Skip to main content
Log in

Donor interleukin 6 gene polymorphisms predict the recurrence of hepatocellular carcinoma after liver transplantation

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Application of the Milan criteria is an effective strategy to select patients with hepatocellular carcinoma (HCC) for liver transplantation, but HCC recurrence is still a major concern. The aim of this study was to determine whether interleukin 6 (IL6) polymorphisms and clinical variables are potential predictors for HCC recurrence and prognosis after transplantation.

Methods

A total of 110 consecutive patients with HCC undergoing liver transplantation were enrolled in the study. Six tag single nucleotide polymorphisms in IL6 were genotyped in both the donors and recipients. Demographic characteristics, HCC features, and IL6 polymorphisms were assessed against HCC recurrence.

Results

Pretransplant hepatitis B virus DNA (P = 0.014), pretransplant serum alpha-fetoprotein (P = 0.035), number of nodules (P = 0.011), diameter of main nodule (P = 0.001), macrovascular invasion (P = 0.001), microvascular invasion (P = 0.001), HCC exceeding the Milan criteria (P < 0.001), and donor rs2069852 AA genotype (P = 0.010) were associated with HCC recurrence. Recurrence-free survival rate and overall survival rate were significantly lower (P = 0.011 and P = 0.026, respectively) in patients whose donor had the rs2069852 AA genotype than in those whose donor had the AG and GG genotypes. Independent risk factors for recurrence-free survival and overall survival were microvascular invasion (P = 0.003; P = 0.002), HCC exceeding the Milan criteria (P < 0.001; P = 0.001), and donor rs2069852 AA genotype (P = 0.002; P = 0.010).

Conclusions

Our data suggest that donor IL6 rs2069852 polymorphisms may be a potential genetic marker for HCC recurrence after liver transplantation in the Han Chinese population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Lafaro KJ, Demirjian AN, Pawlik TM (2015) Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 24:1–17

    Article  PubMed  Google Scholar 

  2. Zimmerman MA, Ghobrial RM, Tong MJ et al (2008) Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg 143:182–188

    Article  PubMed  Google Scholar 

  3. Fong ZV, Tanabe KK (2014) The clinical management of hepatocellular carcinoma in the United States, Europe, and Asia: a comprehensive and evidence-based comparison and review. Cancer 120:2824–2838

    Article  PubMed  Google Scholar 

  4. Bruix J, Gores GJ, Mazzaferro V (2014) Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 63:844–855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lai Q, Avolio AW, Lerut J et al (2012) Recurrence of hepatocellular cancer after liver transplantation: the role of primary resection and salvage transplantation in East and West. J Hepatol 57:974–979

    Article  PubMed  Google Scholar 

  6. Rodriguez-Peralvarez M, Tsochatzis E, Naveas MC et al (2013) Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma. J Hepatol 59:1193–1199

    Article  CAS  PubMed  Google Scholar 

  7. Welker MW, Bechstein WO, Zeuzem S et al (2013) Recurrent hepatocellular carcinoma after liver transplantation—an emerging clinical challenge. Transpl Int 26:109–118

    Article  PubMed  Google Scholar 

  8. Zheng Z, Gao S, Yang Z et al (2014) Single nucleotide polymorphisms in the metastasis-associated in colon cancer-1 gene predict the recurrence of hepatocellular carcinoma after transplantation. Int J Med Sci 11:142–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dickmann LJ, Patel SK, Rock DA et al (2011) Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture. Drug Metab Dispos 39:1415–1422

    Article  CAS  PubMed  Google Scholar 

  10. Yao J, Feng XW, Yu XB et al (2013) Recipient IL-6-572C/G genotype is associated with reduced incidence of acute rejection following liver transplantation. J Int Med Res 41:356–364

    Article  CAS  PubMed  Google Scholar 

  11. Taub R (2004) Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 5:836–847

    Article  CAS  PubMed  Google Scholar 

  12. Ohishi W, Cologne JB, Fujiwara S et al (2014) Serum interleukin-6 associated with hepatocellular carcinoma risk: a nested case-control study. Int J Cancer 134:154–163

    Article  PubMed  Google Scholar 

  13. Liu Y, Gao SJ, Du BX et al (2014) Association of IL-6 polymorphisms with hepatocellular carcinoma risk: evidences from a meta-analysis. Tumour Biol 35:3551–3561

    Article  CAS  PubMed  Google Scholar 

  14. Falleti E, Fabris C, Toniutto P et al (2009) Interleukin-6 polymorphisms and gender: relationship with the occurrence of hepatocellular carcinoma in patients with end-stage liver disease. Oncology 77:304–313

    Article  CAS  PubMed  Google Scholar 

  15. Fan J, Yang GS, Fu ZR et al (2009) Liver transplantation outcomes in 1,078 hepatocellular carcinoma patients: a multi-center experience in Shanghai, China. J Cancer Res Clin Oncol 135:1403–1412

    Article  PubMed  Google Scholar 

  16. Mazzaferro V, Regalia E, Doci R et al (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693–699

    Article  CAS  PubMed  Google Scholar 

  17. Lai Q, Lerut JP (2014) Hepatocellular cancer: how to expand safely inclusion criteria for liver transplantation. Curr Opin Organ Transplant 19:229–234

    Article  CAS  PubMed  Google Scholar 

  18. Takada Y, Tohyama T, Watanabe J (2015) Biological markers of hepatocellular carcinoma for use as selection criteria in liver transplantation. J Hepato Biliary Pancreat Sci 22:279–286

    Article  Google Scholar 

  19. Yao FY, Ferrell L, Bass NM et al (2001) Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 33:1394–1403

    Article  CAS  PubMed  Google Scholar 

  20. DuBay D, Sandroussi C, Sandhu L et al (2011) Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann Surg 253:166–172

    Article  PubMed  Google Scholar 

  21. Clavien PA, Lesurtel M, Bossuyt PM et al (2012) Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 13:e11–e22

    Article  PubMed  Google Scholar 

  22. Li MR, Chen GH, Cai CJ et al (2011) High hepatitis B virus DNA level in serum before liver transplantation increases the risk of hepatocellular carcinoma recurrence. Digestion 84:134–141

    Article  CAS  PubMed  Google Scholar 

  23. Han SH, Reddy KR, Keeffe EB et al (2011) Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study. Clin Transplant 25:E152–E162

    Article  PubMed  Google Scholar 

  24. Fitzmorris P, Shoreibah M, Anand BS et al (2015) Management of hepatocellular carcinoma. J Cancer Res Clin Oncol 141:861–876

    Article  CAS  PubMed  Google Scholar 

  25. Duvoux C, Roudot-Thoraval F, Decaens T et al (2012) Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria. Gastroenterology 143:986–994 (e983; quiz e914–985)

    Article  CAS  PubMed  Google Scholar 

  26. Iguchi T, Shirabe K, Aishima S et al (2015) New pathologic stratification of microvascular invasion in hepatocellular carcinoma: predicting prognosis after living-donor liver transplantation. Transplantation 99:1236–1242

    Article  CAS  PubMed  Google Scholar 

  27. Rodriguez-Peralvarez M, Luong TV, Andreana L et al (2013) A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic variability. Ann Surg Oncol 20:325–339

    Article  PubMed  Google Scholar 

  28. Suo GJ, Zhao ZX (2013) Association of the interleukin-28B gene polymorphism with development of hepatitis virus-related hepatocellular carcinoma and liver cirrhosis: a meta-analysis. Genet Mol Res 12:3708–3717

    Article  CAS  PubMed  Google Scholar 

  29. Wei YG, Liu F, Li B et al (2011) Interleukin-10 gene polymorphisms and hepatocellular carcinoma susceptibility: a meta-analysis. World J Gastroenterol 17:3941–3947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wei Y, Liu F, Li B et al (2011) Polymorphisms of tumor necrosis factor-alpha and hepatocellular carcinoma risk: a HuGE systematic review and meta-analysis. Dig Dis Sci 56:2227–2236

    Article  CAS  PubMed  Google Scholar 

  31. Li S, Deng Y, Chen ZP et al (2011) Genetic polymorphism of interleukin-16 influences susceptibility to HBV-related hepatocellular carcinoma in a Chinese population. Infect Genet Evol 11:2083–2088

    Article  CAS  PubMed  Google Scholar 

  32. Taki-Eldin A, Zhou L, Xie HY et al (2012) Liver regeneration after liver transplantation. Eur Surg Res 48:139–153

    Article  CAS  PubMed  Google Scholar 

  33. Johnson C, Han Y, Hughart N et al (2012) Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer. Transl Gastrointest Cancer 1:58–70

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Naugler WE, Sakurai T, Kim S et al (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–124

    Article  CAS  PubMed  Google Scholar 

  35. Karimi MH, Daneshmandi S, Pourfathollah AA et al (2011) Association of IL-6 promoter and IFN-gamma gene polymorphisms with acute rejection of liver transplantation. Mol Biol Rep 38:4437–4443

    Article  CAS  PubMed  Google Scholar 

  36. Zhang G, Zhou B, Wang W et al (2012) A functional single-nucleotide polymorphism in the promoter of the gene encoding interleukin 6 is associated with susceptibility to tuberculosis. J Infect Dis 205:1697–1704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Komatsu Y, Tai H, Galicia JC et al (2005) Interleukin-6 (IL-6)–373 A9T11 allele is associated with reduced susceptibility to chronic periodontitis in Japanese subjects and decreased serum IL-6 level. Tissue Antigens 65:110–114

    Article  CAS  PubMed  Google Scholar 

  38. Brull DJ, Montgomery HE, Sanders J et al (2001) Interleukin-6 gene −174 g > c and −572 g > c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol 21:1458–1463

    Article  CAS  PubMed  Google Scholar 

  39. Wu LM, Zhou L, Xu J et al (2013) Lack of association between genetic polymorphisms in cytokine genes and tumor recurrence in patients with hepatocellular carcinoma undergoing transplantation. Hepatobiliary Pancreat Dis Int 12:54–59

    Article  CAS  PubMed  Google Scholar 

  40. Norris CA, He M, Kang LI et al (2014) Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli. PLoS One 9:e96053

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhang Y, Shi ZL, Yang X et al (2014) Targeting of circulating hepatocellular carcinoma cells to prevent postoperative recurrence and metastasis. World J Gastroenterol 20:142–147

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the Scientific Research Project of Science and Technology Commission of Shanghai Municipality (No. 134119a6300).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Junwei Fan or Zhihai Peng.

Ethics declarations

Conflict of interest

No author has any conflict of interest.

Ethics statement

Written informed consent forms were obtained from all donors and recipients. The study was approved by the Ethics Committee of Shanghai Jiao Tong University and was conducted strictly under the guidelines of the Declaration of Helsinki.

Additional information

D. Chen and S. Liu are contributed equally to this work.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, D., Liu, S., Chen, S. et al. Donor interleukin 6 gene polymorphisms predict the recurrence of hepatocellular carcinoma after liver transplantation. Int J Clin Oncol 21, 1111–1119 (2016). https://doi.org/10.1007/s10147-016-1001-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-016-1001-1

Keywords

Navigation