Journal of Gastroenterology

, Volume 54, Issue 4, pp 339–346 | Cite as

TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy

  • Etsuko Iio
  • Kentaro Matsuura
  • Noritomo Shimada
  • Masanori Atsukawa
  • Norio Itokawa
  • Hiroshi Abe
  • Keizo Kato
  • Koichi Takaguchi
  • Tomonori Senoh
  • Yuichiro Eguchi
  • Hideyuki Nomura
  • Kai Yoshizawa
  • Jong-Hon Kang
  • Takeshi Matsui
  • Noboru Hirashima
  • Atsunori Kusakabe
  • Tomokatsu Miyaki
  • Kei Fujiwara
  • Kayoko Matsunami
  • Susumu Tsutsumi
  • Katsuhiko Iwakiri
  • Yasuhito TanakaEmail author
Original Article—Liver, Pancreas, and Biliary Tract



The aim of this study is to ascertain whether the TLL1 variant at rs17047200 is associated with the development of HCC after achieving sustained virological response (SVR) by interferon (IFN)-free therapy for chronic hepatitis C (CHC).


A total of 1029 Japanese CHC patients with the following inclusion criteria were enrolled: (i) achieved SVR by IFN-free therapy, (ii) followed up at least 1 year from the end of treatment (EOT) (median 104 weeks), (iii) no history of hepatocellular carcinoma (HCC) by 1 year from the EOT.


Nineteen patients developed HCC (HCC group) and 1010 did not (non-HCC group). The proportion of rs17047200 AT/TT was significantly higher in the HCC group than the non-HCC group (47.4% vs. 20.1%, P = 0.008). Multivariate analysis showed that higher levels of α-fetoprotein, FIB-4 and rs17047200 AT/TT were independent risk factors for developing HCC (HR = 3.22, P = 0.021 for α-fetoprotein > 4.6 ng/ml; HR = 3.89, P = 0.036 for FIB-4 > 2.67; HR = 2.80, P = 0.026 for rs17047200 AT/TT). Cumulative incidence of HCC was significantly higher in patients with rs17047200 AT/TT than in those with AA (P = 0.006). Comparing clinical characteristics according to the TLL1 genotypes, patients with rs17047200 AT/TT had significantly lower platelet counts and higher levels of FIB-4 than those with AA (P = 0.011 and 0.032, respectively).


The TLL1 variant was independently associated with HCC development after HCV eradication by IFN-free regimen. It might be involved in hepatic fibrogenesis and thereby carcinogenesis.


HCV IFN-free therapy TLL1 SVR HCC DAA 





Alanine aminotransaminase


Aspartate aminotransferase


Chronic hepatitis C


Direct-acting antiviral agent


End of treatment


Hepatocellular carcinoma


Hepatitis C virus




Liver cirrhosis


Single nucleotide polymorphism


Sustained virological responses



The authors would like to thank Shintaro Ogawa and Kyoko Ito of Nagoya City University Graduate School of Medical Sciences.


This research was supported by the Research Program on Hepatitis from the Japan Agency for Medical Research and Development (AMED) to Yasuhito Tanka, project code: JP18fk0210001h0003 and the JSPS KAKENHI Grant-in-Aid for Young Scientists (A) to Etsuko Iio, Grant Number: 17K15960

Compliance with ethical standards

Conflict of interest

Yasuhito Tanaka is currently conducting research sponsored by Chugai Pharmaceutical Co., Ltd and has received honoraria from Janssen Pharmaceutical K.K, and Gilead Sciences. Masanori Atsukawa is currently conducting research sponsored by MSD K.K., and AbbVie Inc., and has received honoraria from MSD K.K. and Gilead Sciences. Koichi Takaguchi has received honoraria from Gilead Sciences, MSD K.K., AbbVie Inc., Bristol-Myers Squibb, and Astrazeneka KK. Hideyuki Nomura has received honoraria from Gilead Sciences. The other authors declare no conflicts of interest.


  1. 1.
    Ogawa E, Furusyo N, Nomura H, et al. NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b. J Gastroenterol. 2017;52:845–54.CrossRefGoogle Scholar
  2. 2.
    Iio E, Shimada N, Takaguchi K, et al. Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy. Hepatol Res. 2017;47:1308–16.CrossRefGoogle Scholar
  3. 3.
    Waziry R, Hajarizadeh B, Grebely J, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J Hepatol. 2017;67:1204–12.CrossRefGoogle Scholar
  4. 4.
    Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol. 2017;68:25–32.CrossRefGoogle Scholar
  5. 5.
    Nagata H, Nakagawa M, Asahina Y, et al. Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. J Hepatol. 2017;67:933–9.CrossRefGoogle Scholar
  6. 6.
    Hiramatsu N, Oze T, Takehara T. Suppression of hepatocellular carcinoma development in hepatitis C patients given interferon-based antiviral therapy. Hepatol Res. 2014;45:152–61.CrossRefGoogle Scholar
  7. 7.
    Makiyama A, Itoh Y, Kasahara A, et al. Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma after a sustained response to interferon therapy. Cancer. 2004;101:1616–22.CrossRefGoogle Scholar
  8. 8.
    Chang KC, Hung CH, Lu SN, et al. A novel predictive score for hepatocellular carcinoma development in patients with chronic hepatitis C after sustained response to pegylated interferon and ribavirin combination therapy. J Antimicrob Chemother. 2012;67:2766–72.CrossRefGoogle Scholar
  9. 9.
    Sato A, Sata M, Ikeda K, et al. Clinical characteristics of patients who developed hepatocellular carcinoma after hepatitis C virus eradication with interferon therapy: current status in Japan. Intern Med. 2013;52:2701–6.CrossRefGoogle Scholar
  10. 10.
    Arase Y, Kobayashi M, Suzuki F, et al. Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C. Hepatology. 2013;57:964–73.CrossRefGoogle Scholar
  11. 11.
    El-Serag HB, Kanwal F, Richardson P, et al. Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection. Hepatology. 2016;64:130–7.CrossRefGoogle Scholar
  12. 12.
    Ogawa E, Furusyo N, Kajiwara E, et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: a prospective, multicenter study. J Hepatol. 2013;58:495–501.CrossRefGoogle Scholar
  13. 13.
    Asahina Y, Tsuchiya K, Nishimura T, et al. alpha-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology. 2013;58:1253–62.CrossRefGoogle Scholar
  14. 14.
    Oze T, Hiramatsu N, Yakushijin T, et al. Post-treatment levels of alpha-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy. Clin Gastroenterol Hepatol. 2014;12:1186–95.CrossRefGoogle Scholar
  15. 15.
    Huang CF, Yeh ML, Tsai PC, et al. Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in non-cirrhotic patients with successful hepatitis C virus eradication. J Hepatol. 2014;61:67–74.CrossRefGoogle Scholar
  16. 16.
    Huang CF, Yeh ML, Huang CY, et al. Pretreatment glucose status determines HCC development in HCV patients with mild liver disease after curative antiviral therapy. Med (Baltimore). 2016;95:e4157.CrossRefGoogle Scholar
  17. 17.
    Yu ML, Lin SM, Lee CM, et al. A simple noninvasive index for predicting long-term outcome of chronic hepatitis C after interferon-based therapy. Hepatology. 2006;44:1086–97.CrossRefGoogle Scholar
  18. 18.
    Matsuura K, Sawai H, Ikeo K, et al. Genome-wide association study identifies TLL1 variant associated with development of Hepatocellular Carcinoma after eradication of hepatitis C virus infection. Gastroenterology. 2017;152:1383–94.CrossRefGoogle Scholar
  19. 19.
    Yasui Y, Kurosaki M, Komiyama Y, et al. Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts early occurrence of hepatocellular carcinoma after SVR by direct acting antivirals for HCV. Hepatol Res. 2018. Scholar
  20. 20.
    Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.CrossRefGoogle Scholar
  21. 21.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefGoogle Scholar
  22. 22.
    Matsuura K, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis C virus infection. J Med Virol. 2016;88:185–95.CrossRefGoogle Scholar
  23. 23.
    Matsuura K, Tanaka Y. Host genetic variations associated with disease progression in chronic hepatitis C virus infection. Hepatol Res. 2018;48:127–33.CrossRefGoogle Scholar
  24. 24.
    Patin E, Kutalik Z, Guergnon J, et al. Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection. Gastroenterology. 2012;143(1244–52):e1–12.Google Scholar
  25. 25.
    Urabe Y, Ochi H, Kato N, et al. A genome-wide association study of HCV-induced liver cirrhosis in the Japanese population identifies novel susceptibility loci at the MHC region. J Hepatol. 2013;58:875–82.CrossRefGoogle Scholar
  26. 26.
    Kumar V, Kato N, Urabe Y, et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet. 2011;43:455–8.CrossRefGoogle Scholar
  27. 27.
    Miki D, Ochi H, Hayes CN, et al. Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nat Genet. 2011;43:797–800.CrossRefGoogle Scholar
  28. 28.
    Rattenholl A, Pappano WN, Koch M, et al. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen. J Biol Chem. 2002;277:26372–8.CrossRefGoogle Scholar
  29. 29.
    Veitch DP, Nokelainen P, McGowan KA, et al. Mammalian tolloid metalloproteinase, and not matrix metalloprotease 2 or membrane type 1 metalloprotease, processes laminin-5 in keratinocytes and skin. J Biol Chem. 2003;278:15661–8.CrossRefGoogle Scholar
  30. 30.
    Ge G, Seo NS, Liang X, et al. Bone morphogenetic protein-1/tolloid-related metalloproteinases process osteoglycin and enhance its ability to regulate collagen fibrillogenesis. J Biol Chem. 2004;279:41626–33.CrossRefGoogle Scholar
  31. 31.
    Gonzalez EM, Reed CC, Bix G, et al. BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. J Biol Chem. 2005;280:7080–7.CrossRefGoogle Scholar
  32. 32.
    Kessler E, Takahara K, Biniaminov L, et al. Bone morphogenetic protein-1: the type I procollagen C-proteinase. Science. 1996;271:360–2.CrossRefGoogle Scholar
  33. 33.
    Ge G, Greenspan DS. BMP1 controls TGFbeta1 activation via cleavage of latent TGFbeta-binding protein. J Cell Biol. 2006;175:111–20.CrossRefGoogle Scholar
  34. 34.
    Aihara T, Noguchi S, Sasaki Y, et al. Clonal analysis of regenerative nodules in hepatitis C virus-induced liver cirrhosis. Gastroenterology. 1994;107:1805–11.CrossRefGoogle Scholar
  35. 35.
    Seko Y, Yamaguchi K, Mizuno N, et al. Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease. J Gastroenterol. 2018;53:438–48.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2018

Authors and Affiliations

  • Etsuko Iio
    • 1
  • Kentaro Matsuura
    • 1
  • Noritomo Shimada
    • 2
  • Masanori Atsukawa
    • 3
  • Norio Itokawa
    • 4
  • Hiroshi Abe
    • 5
  • Keizo Kato
    • 5
  • Koichi Takaguchi
    • 6
  • Tomonori Senoh
    • 6
  • Yuichiro Eguchi
    • 7
  • Hideyuki Nomura
    • 8
  • Kai Yoshizawa
    • 9
  • Jong-Hon Kang
    • 10
  • Takeshi Matsui
    • 10
  • Noboru Hirashima
    • 11
  • Atsunori Kusakabe
    • 12
  • Tomokatsu Miyaki
    • 13
  • Kei Fujiwara
    • 1
  • Kayoko Matsunami
    • 1
  • Susumu Tsutsumi
    • 1
  • Katsuhiko Iwakiri
    • 3
  • Yasuhito Tanaka
    • 1
    Email author
  1. 1.Nagoya City University, Graduate School of Medical SciencesNagoyaJapan
  2. 2.Ootakanomori HospitalKashiwaJapan
  3. 3.Nippon Medical School HospitalTokyoJapan
  4. 4.Nippon Medical School Chiba Hokusoh HospitalChibaJapan
  5. 5.Shinmatsudo Central General HospitalChibaJapan
  6. 6.Kagawa Prefectural Central HospitalTakamatsuJapan
  7. 7.Saga University HospitalSagaJapan
  8. 8.Shin-Kokura HospitalKitakyushuJapan
  9. 9.Machida Municipal HospitalTokyoJapan
  10. 10.Teine Keijinkai HospitalSapporoJapan
  11. 11.National Hospital Organization Nagoya Medical CenterNagoyaJapan
  12. 12.Japanese Red Cross Nagoya Daini HospitalNagoyaJapan
  13. 13.Toyokawa City HospitalToyokawaJapan

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