Advertisement

Tumor Biology

, Volume 36, Issue 10, pp 7807–7815 | Cite as

Association between donor and recipient smoothened gene polymorphisms and the risk of hepatocellular carcinoma recurrence following orthotopic liver transplantation in a Han Chinese population

Research Article

Abstract

Hepatocellular carcinoma (HCC) recurrence after orthotopic liver transplantation (OLT) is potential cause for the poor outcome. Smoothened (SMO) gene has been considered associating with HCC and HCC recurrence, but its association with HCC recurrence after OLT is not clear yet. In this study, we aim at evaluating the association between donor and recipient SMO gene polymorphisms and HCC recurrence after OLT. A total of 76 patients with HCC who had undergone OLT from July 2007 to August 2012 were included. A single nucleotide polymorphism (SNP), SMO rs3824, located at the 3′UTR region, was genotyped and analyzed in both donor and recipient. We demonstrated that recipient rs3824 polymorphism was significantly associated with HCC recurrence following OLT. In multivariate logistic regression analysis, TNM stage (p = 0.001), recipient SMO rs3824 genotype (CG vs. CC/GG p = 0.001), and histologic grade (p = 0.019) were identified as independent risk factors of HCC recurrence. Recurrence-free survival (RFS) and overall survival (OS) were significantly higher in the recipient CC/GG group than in the CG group (p = 0.003 and p = 0.011, respectively). Cox proportional hazards modeling revealed that TNM stage, recipient SMO rs3824 genotype, pre-OLT serum AFP level, and histologic grade were independent factors (p < 0.05) for patients’ clinical outcomes. In conclusion, recipient SMO rs3824 polymorphism is associated with an increased risk of HCC recurrence following OLT and has a potential clinical value for the prognosis of HCC patients treated with OLT.

Keywords

SMO polymorphism Hepatocellular carcinoma Recurrence Orthotopic liver transplantation Prognosis 

Notes

Acknowledgments

This study was partly supported by a grant from the Nature Science Foundation of Shanghai (13JC1404600).

Conflicts of interest

None

References

  1. 1.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76. doi: 10.1053/j.gastro.2007.04.061.CrossRefPubMedGoogle Scholar
  2. 2.
    Tang ZY, Ye SL, Liu YK, Qin LX, Sun HC, Ye QH, et al. A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130(4):187–96. doi: 10.1007/s00432-003-0511-1.CrossRefPubMedGoogle Scholar
  3. 3.
    Lee KK, Kim DG, Moon IS, Lee MD, Park JH. Liver transplantation versus liver resection for the treatment of hepatocellular carcinoma. J Surg Oncol. 2010;101(1):47–53. doi: 10.1002/jso.21415.CrossRefPubMedGoogle Scholar
  4. 4.
    Zimmerman MA, Ghobrial RM, Tong MJ, Hiatt JR, Cameron AM, Hong J, et al. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg. 2008;143(2):182–8. doi: 10.1001/archsurg.2007.39. discussion 8.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen J, Xu X, Wu J, Ling Q, Wang K, Wang W, et al. The stratifying value of Hangzhou criteria in liver transplantation for hepatocellular carcinoma. PLoS One. 2014;9(3):e93128. doi: 10.1371/journal.pone.0093128.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mazzaferro V, Chun YS, Poon RT, Schwartz ME, Yao FY, Marsh JW, et al. Liver transplantation for hepatocellular carcinoma. Ann Surg Oncol. 2008;15(4):1001–7. doi: 10.1245/s10434-007-9559-5.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33(6):1394–403. doi: 10.1053/jhep.2001.24563.CrossRefPubMedGoogle Scholar
  8. 8.
    Nagai S, Yoshida A, Facciuto M, Moonka D, Abouljoud MS, Schwartz ME, et al. Ischemia time impacts recurrence of hepatocellular carcinoma following liver transplantation. Hepatology. 2014. doi: 10.1002/hep.27358.PubMedGoogle Scholar
  9. 9.
    Brastianos PK, Horowitz PM, Santagata S, Jones RT, McKenna A, Getz G, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet. 2013;45(3):285–9. doi: 10.1038/ng.2526.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wang C, Wu H, Katritch V, Han GW, Huang XP, Liu W, et al. Structure of the human smoothened receptor bound to an antitumour agent. Nature. 2013;497(7449):338–43. doi: 10.1038/nature12167.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Che L, Yuan YH, Jia J, Ren J. Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients. Chin J Cancer Res = Chung-Kuo Yen Cheng Yen Chiu. 2012;24(4):323–31. doi: 10.3978/j.issn.1000-9604.2012.10.10.CrossRefPubMedGoogle Scholar
  12. 12.
    Huang S, He J, Zhang X, Bian Y, Yang L, Xie G, et al. Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis. 2006;27(7):1334–40. doi: 10.1093/carcin/bgi378.CrossRefPubMedGoogle Scholar
  13. 13.
    Kim Y, Yoon JW, Xiao X, Dean NM, Monia BP, Marcusson EG. Selective down-regulation of glioma-associated oncogene 2 inhibits the proliferation of hepatocellular carcinoma cells. Cancer Res. 2007;67(8):3583–93. doi: 10.1158/0008-5472.CAN-06-3040.CrossRefPubMedGoogle Scholar
  14. 14.
    Jeng KS, Sheen IS, Jeng WJ, Lin CC, Lin CK, Su JC, et al. High expression of patched homolog-1 messenger RNA and glioma-associated oncogene-1 messenger RNA of sonic hedgehog signaling pathway indicates a risk of postresection recurrence of hepatocellular carcinoma. Ann Surg Oncol. 2013;20(2):464–73. doi: 10.1245/s10434-012-2593-y.CrossRefPubMedGoogle Scholar
  15. 15.
    Philips GM, Chan IS, Swiderska M, Schroder VT, Guy C, Karaca GF, et al. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. PLoS One. 2011;6(9):e23943. doi: 10.1371/journal.pone.0023943.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Xu Y, Chenna V, Hu C, Sun HX, Khan M, Bai H, et al. Polymeric nanoparticle-encapsulated hedgehog pathway inhibitor HPI-1 (NanoHHI) inhibits systemic metastases in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res : Off J Am Assoc Cancer Res. 2012;18(5):1291–302. doi: 10.1158/1078-0432.CCR-11-0950.CrossRefGoogle Scholar
  17. 17.
    Mao J, Fan PH, Ma W, Zhang QQ, Wang B, Fan SJ, et al. Down-regulation of Smoothened gene expression inhibits proliferation of breast cancer stem cells. Zhonghua Bing Li Xue Za Zhi Chin J Pathol. 2013;42(4):262–6. doi: 10.3760/cma.j.issn.0529-5807.2013.04.011.Google Scholar
  18. 18.
    Ruat M, Hoch L, Faure H, Rognan D. Targeting of Smoothened for therapeutic gain. Trends Pharmacol Sci. 2014;35(5):237–46. doi: 10.1016/j.tips.2014.03.002.CrossRefPubMedGoogle Scholar
  19. 19.
    Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant : Off J Am Soc Transplant Am Soc Transplant Surg. 2006;6(4):783–90. doi: 10.1111/j.1600-6143.2006.01242.x.CrossRefGoogle Scholar
  20. 20.
    Segev DL, Maley WR, Simpkins CE, Locke JE, Nguyen GC, Montgomery RA, et al. Minimizing risk associated with elderly liver donors by matching to preferred recipients. Hepatology. 2007;46(6):1907–18. doi: 10.1002/hep.21888.CrossRefPubMedGoogle Scholar
  21. 21.
    Shores NJ, Dodge JL, Feng S, Terrault NA. Donor Risk Index for African American liver transplant recipients with hepatitis C virus. Hepatology. 2013;58(4):1263–9. doi: 10.1002/hep.26478.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    World Medical Association declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. JAMA. 1997;277(11):925–6.CrossRefGoogle Scholar
  23. 23.
    Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4.Google Scholar
  24. 24.
    Zheng SS, Xu X, Wu J, Chen J, Wang WL, Zhang M, et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation. 2008;85(12):1726–32. doi: 10.1097/TP.0b013e31816b67e4.CrossRefPubMedGoogle Scholar
  25. 25.
    Gabriel S, Ziaugra L, Tabbaa D. SNP genotyping using the Sequenom MassARRAY iPLEX platform. Current protocols in human genetics/editorial board, Jonathan L Haines et al. 2009;Chapter 2:Unit 2 12. doi: 10.1002/0471142905.hg0212s60.
  26. 26.
    Hameed B, Mehta N, Sapisochin G, Roberts JP, Yao FY. Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transpl. 2014;20(8):945–51. doi: 10.1002/lt.23904.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Li WX, Li Z, Gao PJ, Gao J, Zhu JY. Histological differentiation predicts post-liver transplantation survival time. Clin Res Hepatol Gastroenterol. 2014;38(2):201–8. doi: 10.1016/j.clinre.2013.11.002.CrossRefPubMedGoogle Scholar
  28. 28.
    Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22(18):2454–72. doi: 10.1101/gad.1693608.CrossRefPubMedGoogle Scholar
  29. 29.
    Pricl S, Cortelazzi B, Dal Col V, Marson D, Laurini E, Fermeglia M, et al. Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma. Mol Oncol. 2014. doi: 10.1016/j.molonc.2014.09.003.PubMedGoogle Scholar
  30. 30.
    Liao PY, Lee KH. From SNPs to functional polymorphism: The insight into biotechnology applications. Biochem Eng J. 2010;49(2):149–58. doi: 10.1016/j.bej.2009.12.021.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of General Surgery, Affiliated First People’s HospitalShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Department of General SurgeryThe First People’s Hospital of Yongkang CityYongkang CityChina
  3. 3.Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation, The first Affiliated HospitalZhengzhou UniversityZhengzhouChina

Personalised recommendations