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.
SMO polymorphism Hepatocellular carcinoma Recurrence Orthotopic liver transplantation Prognosis
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This study was partly supported by a grant from the Nature Science Foundation of Shanghai (13JC1404600).
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
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
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
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
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
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
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
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.
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