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  • Review Article
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The role of telomeres and telomerase in cirrhosis and liver cancer

Abstract

Telomerase is a key enzyme for cell survival that prevents telomere shortening and the subsequent cellular senescence that is observed after many rounds of cell division. In contrast, inactivation of telomerase is observed in most cells of the adult liver. Absence of telomerase activity and shortening of telomeres has been implicated in hepatocyte senescence and the development of cirrhosis, a chronic liver disease that can lead to hepatocellular carcinoma (HCC) development. During hepatocarcinogenesis, telomerase reactivation is required to enable the uncontrolled cell proliferation that leads to malignant transformation and HCC development. Part of the telomerase complex, telomerase reverse transcriptase, is encoded by TERT, and several mechanisms of telomerase reactivation have been described in HCC that include somatic TERT promoter mutations, TERT amplification, TERT translocation and viral insertion into the TERT gene. An understanding of the role of telomeres and telomerase in HCC development is important to develop future targeted therapies and improve survival of this disease. In this Review, the roles of telomeres and telomerase in liver carcinogenesis are discussed, in addition to their potential translation to clinical practice as biomarkers and therapeutic targets.

Key points

  • Telomerase is a key enzyme for cell survival that prevents telomere shortening after cell divisions.

  • Cirrhosis is characterized by replicative senescence owing to short telomeres and no telomerase expression (TERT gene) in mature hepatocytes.

  • A return of telomerase expression is observed in 90% of hepatocellular carcinomas (HCC).

  • Mechanisms of telomerase reactivation in HCC are related to TERT promoter mutations, TERT amplification, chromosome translocations and HBV or adeno-associated virus type 2 viral insertion into the TERT promoter.

  • Several biomarkers and therapies directed against telomerase are in development, but none of them is currently validated for use in HCC.

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Fig. 1: Telomerase expression and telomere maintenance in the liver.
Fig. 2: Mechanisms of telomere maintenance in liver carcinogenesis.
Fig. 3: TERT promoter mutations across different histological types of cancer in human.
Fig. 4: Role of telomerase reactivation in the multistep process of liver carcinogenesis.
Fig. 5: Telomerase-based cancer therapies.

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References

  1. El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118–1127 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Forner, A., Llovet, J. M. & Bruix, J. Hepatocellular carcinoma. Lancet 379, 1245–1255 (2012).

    Article  PubMed  Google Scholar 

  3. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391, 1163–1173 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Bruix, J. et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J. Hepatol. 57, 821–829 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Abou-Alfa, G. K. et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial [abstract]. J. Clin. Oncol. 36 (Suppl. 4), 207 (2018).

    Article  Google Scholar 

  7. Bruix, J. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389, 56–66 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Llovet, J. M. & Hernandez-Gea, V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin. Cancer Res. 20, 2072–2079 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Pinyol, R., Nault, J. C., Quetglas, I. M., Zucman-Rossi, J. & Llovet, J. M. Molecular profiling of liver tumors: classification and clinical translation for decision making. Semin. Liver Dis. 34, 363–375 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Nault, J. C. Pathogenesis of hepatocellular carcinoma according to aetiology. Best Pract. Res. Clin. Gastroenterol. 28, 937–947 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Zucman-Rossi, J., Villanueva, A., Nault, J. C. & Llovet, J. M. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149, 1226–1239 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Nault, J. C. & Zucman-Rossi, J. Genetics of hepatobiliary carcinogenesis. Semin. Liver Dis. 31, 173–187 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Guichard, C. et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 44, 694–698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schulze, K. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47, 505–511 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schulze, K., Nault, J. C. & Villanueva, A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J. Hepatol. 65, 1031–1042 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fujimoto, A. et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat. Genet. 44, 760–764 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Totoki, Y. et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 46, 1267–1273 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Hoare, M., Das, T. & Alexander, G. Ageing, telomeres, senescence, and liver injury. J. Hepatol. 53, 950–961 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Rudolph, K. L., Hartmann, D. & Opitz, O. G. Telomere dysfunction and DNA damage checkpoints in diseases and cancer of the gastrointestinal tract. Gastroenterology 137, 754–762 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Satyanarayana, A., Manns, M. P. & Rudolph, K. L. Telomeres and telomerase: a dual role in hepatocarcinogenesis. Hepatology 40, 276–283 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Olovnikov, A. M. Principle of marginotomy in template synthesis of polynucleotides [Russian]. Dokl. Akad. Nauk SSSR 201, 1496–1499 (1971).

    CAS  PubMed  Google Scholar 

  23. Blackburn, E. H. Switching and signaling at the telomere. Cell 106, 661–673 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Varela, E. & Blasco, M. A. 2009 Nobel Prize in Physiology or Medicine: telomeres and telomerase. Oncogene 29, 1561–1565 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Shampay, J., Szostak, J. W. & Blackburn, E. H. DNA sequences of telomeres maintained in yeast. Nature 310, 154–157 (1984).

    Article  CAS  PubMed  Google Scholar 

  26. Calado, R. T. & Young, N. S. Telomere diseases. N. Engl. J. Med. 361, 2353–2365 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Smith, F. W. & Feigon, J. Quadruplex structure of Oxytricha telomeric DNA oligonucleotides. Nature 356, 164–168 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. Brown, J. P., Wei, W. & Sedivy, J. M. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277, 831–834 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Stein, G. H., Drullinger, L. F., Soulard, A. & Dulic, V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol. Cell. Biol. 19, 2109–2117 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Counter, C. M. et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11, 1921–1929 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wright, W. E. & Shay, J. W. The two-stage mechanism controlling cellular senescence and immortalization. Exp. Gerontol. 27, 383–389 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    Article  PubMed  CAS  Google Scholar 

  33. Artandi, S. E. & DePinho, R. A. Telomeres and telomerase in cancer. Carcinogenesis 31, 9–18 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Gilson, E. & Geli, V. How telomeres are replicated. Nat. Rev. Mol. Cell Biol. 8, 825–838 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Gunes, C. & Rudolph, K. L. The role of telomeres in stem cells and cancer. Cell 152, 390–393 (2013).

    Article  PubMed  CAS  Google Scholar 

  36. Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Urabe, Y. et al. Telomere length in human liver diseases. Liver 16, 293–297 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Wiemann, S. U. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 16, 935–942 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Paradis, V. et al. Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas. Hum. Pathol. 32, 327–332 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Aravinthan, A. et al. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J. Hepatol. 58, 549–556 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Brunt, E. M., Walsh, S. N., Hayashi, P. H., Labundy, J. & Di Bisceglie, A. M. Hepatocyte senescence in end-stage chronic liver disease: a study of cyclin-dependent kinase inhibitor p21 in liver biopsies as a marker for progression to hepatocellular carcinoma. Liver Int. 27, 662–671 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Aravinthan, A. et al. Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease. PLOS One 8, e72904 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rudolph, K. L., Chang, S., Millard, M., Schreiber-Agus, N. & DePinho, R. A. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 287, 1253–1258 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Hartmann, D. et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology 53, 1608–1617 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Calado, R. T. et al. Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology 53, 1600–1607 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Deng, Y., Chan, S. S. & Chang, S. Telomere dysfunction and tumour suppression: the senescence connection. Nat. Rev. Cancer 8, 450–458 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Patnaik, M. M., Kamath, P. S. & Simonetto, D. A. Hepatic manifestations of telomere biology disorders. J. Hepatol. 69, 736–743 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Carulli, L., Dei Cas, A. & Nascimbeni, F. Synchronous cryptogenic liver cirrhosis and idiopathic pulmonary fibrosis: a clue to telomere involvement. Hepatology 56, 2001–2003 (2012).

    Article  PubMed  Google Scholar 

  49. Gorgy, A. I. et al. Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders. Chest 148, 1019–1026 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ganne-Carrie, N. et al. Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in Western patients with cirrhosis. Hepatology 23, 1112–1118 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Trinchet, J. C. et al. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort). Hepatology 62, 737–750 (2015).

    Article  PubMed  Google Scholar 

  52. Lechel, A. et al. Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology 132, 1465–1475 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Farazi, P. A. et al. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 63, 5021–5027 (2003).

    CAS  PubMed  Google Scholar 

  56. Wiemann, S. U. et al. Contrasting effects of telomere shortening on organ homeostasis, tumor suppression, and survival during chronic liver damage. Oncogene 24, 1501–1509 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Farazi, P. A., Glickman, J., Horner, J. & Depinho, R. A. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res. 66, 4766–4773 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sahin, E. & Depinho, R. A. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464, 520–528 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Farazi, P. A. & DePinho, R. A. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat. Rev. Cancer 6, 674–687 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Plentz, R. R. et al. Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma. Hepatology 40, 80–86 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Meena, J. K. et al. Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion. EMBO J. 34, 1371–1384 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Begus-Nahrmann, Y. et al. Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis. J. Clin. Invest. 122, 2283–2288 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ohashi, K. et al. Telomere changes in human hepatocellular carcinomas and hepatitis virus infected noncancerous livers. Cancer 77, 1747–1751 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Ferlicot, S., Paradis, V., Dargere, D., Monges, G. & Bedossa, P. Detection of telomerase in hepatocellular carcinomas using a PCR ELISA assay: comparison with hTR expression. J. Clin. Pathol. 52, 725–729 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nakayama, J. et al. Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat. Genet. 18, 65–68 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Shimada, M. et al. The role of telomerase activity in hepatocellular carcinoma. Am. J. Gastroenterol. 95, 748–752 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Youssef, N., Paradis, V., Ferlicot, S. & Bedossa, P. In situ detection of telomerase enzymatic activity in human hepatocellular carcinogenesis. J. Pathol. 194, 459–465 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957–959 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bell, R. J. et al. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 348, 1036–1039 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ko, E., Seo, H. W., Jung, E. S., Kim, B. H. & Jung, G. The TERT promoter SNP rs2853669 decreases E2F1 transcription factor binding and increases mortality and recurrence risks in liver cancer. Oncotarget 7, 684–699 (2016).

    Article  PubMed  Google Scholar 

  73. Heidenreich, B., Rachakonda, P. S., Hemminki, K. & Kumar, R. TERT promoter mutations in cancer development. Curr. Opin. Genet. Dev. 24, 30–37 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Chiba, K. et al. Cancer-associated TERT promoter mutations abrogate telomerase silencing. eLife 4, e07918 (2015).

    Article  PubMed Central  Google Scholar 

  75. Borah, S. et al. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science 347, 1006–1010 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chiba, K. et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science 357, 1416–1420 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Killela, P. J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl Acad. Sci. U. S. A. 110, 6021–6026 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Allory, Y. et al. Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome. Eur. Urol. 65, 360–366 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Vinagre, J. et al. Frequency of TERT promoter mutations in human cancers. Nat. Commun. 4, 2185 (2013).

    Article  PubMed  CAS  Google Scholar 

  80. Griewank, K. G. et al. TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma. PLoS One 8, e80354 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Griewank, K. G. et al. TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours. Br. J. Cancer 109, 497–501 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Griewank, K. G. et al. TERT promoter mutations are frequent in atypical fibroxanthomas and pleomorphic dermal sarcomas. Mod. Pathol. 27, 502–508 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Tallet, A. et al. Overexpression and promoter mutation of the TERT gene in malignant pleural mesothelioma. Oncogene 33, 3748–3752 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Barthel, F. P. et al. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat. Genet. 49, 349–357 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Valentijn, L. J. et al. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat. Genet. 47, 1411–1414 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Peifer, M. et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526, 700–704 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Karlsson, J. et al. Activation of human telomerase reverse transcriptase through gene fusion in clear cell sarcoma of the kidney. Cancer Lett. 357, 498–501 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Nault, J. C. et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 4, 2218 (2013).

    Article  PubMed  CAS  Google Scholar 

  89. The Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169, 1327–1341 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  90. Park, J. I. et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460, 66–72 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chen, Y. L. et al. TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection. Int. J. Surg. 12, 659–665 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Quaas, A. et al. Frequency of TERT promoter mutations in primary tumors of the liver. Virchows Arch. 465, 673–677 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Cevik, D., Yildiz, G. & Ozturk, M. Common telomerase reverse transcriptase promoter mutations in hepatocellular carcinomas from different geographical locations. World J. Gastroenterol. 21, 311–317 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Huang, D. S. et al. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur. J. Cancer 51, 969–976 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yang, X. et al. Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma. Oncotarget 7, 27838–27847 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Kawai-Kitahata, F. et al. Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. J. Gastroenterol. 51, 473–486 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. Chianchiano, P. et al. Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations. Hum. Pathol. 72, 127–134 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Torrecilla, S. et al. Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J. Hepatol. 67, 1222–1231 (2017).

    Article  PubMed  Google Scholar 

  99. Lee, S. E. et al. Frequent somatic TERT promoter mutations and CTNNB1 mutations in hepatocellular carcinoma. Oncotarget 7, 69267–69275 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Pezzuto, F. et al. Tumor specific mutations in TERT promoter and CTNNB1 gene in hepatitis B and hepatitis C related hepatocellular carcinoma. Oncotarget 7, 54253–54262 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Letouze, E. et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat. Commun. 8, 1315 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Bayard, Q. et al. Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Nat. Commun. 9, 5235 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Neuveut, C., Wei, Y. & Buendia, M. A. Mechanisms of HBV-related hepatocarcinogenesis. J. Hepatol. 52, 594–604 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Levrero, M. & Zucman-Rossi, J. Mechanisms of HBV-induced hepatocellular carcinoma. J. Hepatol. 64, S84–101 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. Brechot, C., Pourcel, C., Louise, A., Rain, B. & Tiollais, P. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature 286, 533–535 (1980).

    Article  CAS  PubMed  Google Scholar 

  106. Dejean, A., Bougueleret, L., Grzeschik, K. H. & Tiollais, P. Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature 322, 70–72 (1986).

    Article  CAS  PubMed  Google Scholar 

  107. Sung, W. K. et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet. 44, 765–769 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Xue, R. et al. Variable intra-tumor genomic heterogeneity of multiple lesions in patients with hepatocellular carcinoma. Gastroenterology 150, 998–1008 (2016).

    Article  PubMed  Google Scholar 

  109. Zhao, L. H. et al. Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma. Nat. Commun. 7, 12992 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nault, J. C. et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat. Genet. 47, 1187–1193 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Logan, G. J. et al. Identification of liver-specific enhancer-promoter activity in the 3′ untranslated region of the wild-type AAV2 genome. Nat. Genet. 49, 1267–1273 (2017).

    Article  CAS  PubMed  Google Scholar 

  112. Cesare, A. J. & Reddel, R. R. Alternative lengthening of telomeres: models, mechanisms and implications. Nat. Rev. Genet. 11, 319–330 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Heaphy, C. M. et al. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am. J. Pathol. 179, 1608–1615 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bechter, O. E., Zou, Y., Walker, W., Wright, W. E. & Shay, J. W. Telomeric recombination in mismatch repair deficient human colon cancer cells after telomerase inhibition. Cancer Res. 64, 3444–3451 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Heaphy, C. M. et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 333, 425 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lovejoy, C. A. et al. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLOS Genet. 8, e1002772 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wood, L. D. et al. Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features. Mod. Pathol. 26, 1586–1593 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Di Tommaso, L. et al. Advanced precancerous lesions in the liver. Best Pract. Res. Clin. Gastroenterol. 27, 269–284 (2013).

    Article  PubMed  Google Scholar 

  119. Borzio, M. et al. Impact of large regenerative, low grade and high grade dysplastic nodules in hepatocellular carcinoma development. J. Hepatol. 39, 208–214 (2003).

    Article  PubMed  Google Scholar 

  120. Nault, J. C. et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 60, 1983–1992 (2014).

    Article  CAS  PubMed  Google Scholar 

  121. Nault, J. C. et al. Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation. Gastroenterology 152, 880–894 (2017).

    Article  CAS  PubMed  Google Scholar 

  122. Bioulac-Sage, P., Cubel, G., Balabaud, C. & Zucman-Rossi, J. Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers. Semin. Liver Dis. 31, 91–103 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Bluteau, O. et al. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat. Genet. 32, 312–315 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Nault, J. C. et al. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. J. Hepatol. 56, 184–191 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Pilati, C. et al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell 25, 428–441 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Rebouissou, S. et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457, 200–204 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Pilati, C. et al. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J. Exp. Med. 208, 1359–1366 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Nault, J. C. et al. ASS1 and peri-portal gene expression in sonic hedgehog hepatocellular adenomas. Hepatology 68, 964–976 (2018).

    Article  CAS  PubMed  Google Scholar 

  129. Calderaro, J. et al. Systemic AA amyloidosis caused by inflammatory hepatocellular adenoma. N. Engl. J. Med. 379, 1178–1180 (2018).

    Article  PubMed  Google Scholar 

  130. Goutagny, S. et al. High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol. 24, 184–189 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Pestana, A., Vinagre, J., Sobrinho-Simoes, M. & Soares, P. TERT biology and function in cancer: beyond immortalisation. J. Mol. Endocrinol. 58, R129–R146 (2017).

    Article  CAS  PubMed  Google Scholar 

  132. Jung, S. W. et al. Prognostic impact of telomere maintenance gene polymorphisms on hepatocellular carcinoma patients with chronic hepatitis B. Hepatology 59, 1912–1920 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Bao, D. et al. Alterations of telomere length and mtDNA copy number are associated with overall survival in hepatocellular carcinoma patients treated with transarterial chemoembolization. Cancer Chemother. Pharmacol. 78, 791–799 (2016).

    Article  CAS  PubMed  Google Scholar 

  134. Liu, H. Q. et al. Leukocyte telomere length predicts overall survival in hepatocellular carcinoma treated with transarterial chemoembolization. Carcinogenesis 33, 1040–1045 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kobayashi, T., Kubota, K., Takayama, T. & Makuuchi, M. Telomerase activity as a predictive marker for recurrence of hepatocellular carcinoma after hepatectomy. Am. J. Surg. 181, 284–288 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Kobayashi, T., Sugawara, Y., Shi, Y. Z. & Makuuchi, M. Telomerase expression and p53 status in hepatocellular carcinoma. Am. J. Gastroenterol. 97, 3166–3171 (2002).

    Article  CAS  PubMed  Google Scholar 

  137. Oh, B. K. et al. High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis. Lab. Invest. 88, 144–152 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Yu, J. I. et al. Clinical importance of TERT overexpression in hepatocellular carcinoma treated with curative surgical resection in HBV endemic area. Sci. Rep. 7, 12258 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Nakashio, R. et al. Alteration of telomeric repeat length in hepatocellular carcinoma is independent of telomerase activity. Int. J. Oncol. 11, 139–143 (1997).

    CAS  PubMed  Google Scholar 

  140. Kim, H. et al. Telomere length, TERT and shelterin complex proteins in hepatocellular carcinomas expressing “stemness”-related markers. J. Hepatol. 59, 746–752 (2013).

    Article  CAS  PubMed  Google Scholar 

  141. Ma, L. J. et al. Telomere length variation in tumor cells and cancer-associated fibroblasts: potential biomarker for hepatocellular carcinoma. J. Pathol. 243, 407–417 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ko, E., Seo, H. W. & Jung, G. Telomere length and reactive oxygen species levels are positively associated with a high risk of mortality and recurrence in hepatocellular carcinoma. Hepatology 67, 1378–1391 (2018).

    Article  CAS  PubMed  Google Scholar 

  143. Ohta, K. et al. Telomerase activity in hepatocellular carcinoma as a predictor of postoperative recurrence. J. Gastroenterol. 32, 791–796 (1997).

    Article  CAS  PubMed  Google Scholar 

  144. Kanamaru, T. et al. Clinical implications of telomerase activity in resected hepatocellular carcinoma. Int. J. Mol. Med. 4, 267–271 (1999).

    CAS  PubMed  Google Scholar 

  145. Yang, B. et al. Telomere length and survival of patients with hepatocellular carcinoma in the United States. PLOS One 11, e0166828 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Labgaa, I. et al. A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma. Oncogene 37, 3740–3752 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Ruden, M. & Puri, N. Novel anticancer therapeutics targeting telomerase. Cancer Treat. Rev. 39, 444–456 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Harley, C. B. Telomerase and cancer therapeutics. Nat. Rev. Cancer 8, 167–179 (2008).

    Article  CAS  PubMed  Google Scholar 

  149. Djojosubroto, M. W. et al. Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. Hepatology 42, 1127–1136 (2005).

    Article  CAS  PubMed  Google Scholar 

  150. Tefferi, A. et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N. Engl. J. Med. 373, 908–919 (2015).

    Article  CAS  PubMed  Google Scholar 

  151. Baerlocher, G. M. et al. Telomerase inhibitor imetelstat in patients with essential thrombocythemia. N. Engl. J. Med. 373, 920–928 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. Buseman, C. M., Wright, W. E. & Shay, J. W. Is telomerase a viable target in cancer? Mutat. Res. 730, 90–97 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. Geron. Press release: Geron provides update on imetelstat clinical development program. geron http://ir.geron.com/news-releases/news-release-details/geron-provides-update-imetelstat-clinical-development-program (2012).

  154. Chiappori, A. A. et al. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann. Oncol. 26, 354–362 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Salloum, R. et al. A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study. J. Neurooncol. 129, 443–451 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Sundquist, W. I. & Klug, A. Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops. Nature 342, 825–829 (1989).

    Article  CAS  PubMed  Google Scholar 

  157. Burger, A. M. et al. The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. Cancer Res. 65, 1489–1496 (2005).

    Article  CAS  PubMed  Google Scholar 

  158. Salvati, E. et al. Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect. J. Clin. Invest. 117, 3236–3247 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Tauchi, T. et al. Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways. Oncogene 22, 5338–5347 (2003).

    Article  CAS  PubMed  Google Scholar 

  160. Tahtouh, R. et al. Telomerase inhibition decreases alpha-fetoprotein expression and secretion by hepatocellular carcinoma cell lines: in vitro and in vivo study. PLOS One 10, e0119512 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Kotsakis, A. et al. Clinical outcome of patients with various advanced cancer types vaccinated with an optimized cryptic human telomerase reversetranscriptase (TERT) peptide: results of an expanded phase II study. Ann. Oncol. 23, 442–449 (2012).

    Article  CAS  PubMed  Google Scholar 

  162. Brunsvig, P. F. et al. Telomerase peptide vaccination in NSCLC: a phase II trial in stage III patients vaccinated after chemoradiotherapy and an 8-year update on a phase I/II trial. Clin. Cancer Res. 17, 6847–6857 (2011).

    Article  CAS  PubMed  Google Scholar 

  163. Anguille, S., Smits, E. L., Lion, E., van Tendeloo, V. F. & Berneman, Z. N. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 15, e257–e267 (2014).

    Article  CAS  PubMed  Google Scholar 

  164. Greten, T. F. et al. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer 10, 209 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Middleton, G. et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 15, 829–840 (2014).

    Article  CAS  PubMed  Google Scholar 

  166. Gilboa, E. & Vieweg, J. Cancer immunotherapy with mRNA-transfected dendritic cells. Immunol. Rev. 199, 251–263 (2004).

    Article  CAS  PubMed  Google Scholar 

  167. Su, Z. et al. Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J. Immunol. 174, 3798–3807 (2005).

    Article  CAS  PubMed  Google Scholar 

  168. Fenoglio, D. et al. A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer. Cancer Immunol. Immunother. 62, 1041–1052 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Weiss, J. M., Subleski, J. J., Wigginton, J. M. & Wiltrout, R. H. Immunotherapy of cancer by IL-12-based cytokine combinations. Expert Opin. Biol. Ther. 7, 1705–1721 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02960594 (2018).

  171. Zhang, Y. et al. AAV-mediated TRAIL gene expression driven by hTERT promoter suppressed human hepatocellular carcinoma growth in mice. Life Sci. 82, 1154–1161 (2008).

    Article  CAS  PubMed  Google Scholar 

  172. Lanson, N. A. et al. Replication of an adenoviral vector controlled by the human telomerase reverse transcriptase promoter causes tumor-selective tumor lysis. Cancer Res. 63, 7936–7941 (2003).

    CAS  PubMed  Google Scholar 

  173. Nemunaitis, J. et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol. Ther. 18, 429–434 (2010).

    Article  CAS  PubMed  Google Scholar 

  174. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03190824 (2019).

  175. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03213054 (2018).

  176. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03172819 (2018).

  177. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02293850 (2018).

  178. Chaklader, M. et al. 17-AAG mediated targeting of Hsp90 limits tert activity in peritoneal sarcoma related malignant ascites by downregulating cyclin D1 during cell cycle entry. Exp. Oncol. 34, 90–96 (2012).

    CAS  PubMed  Google Scholar 

  179. Seimiya, H., Muramatsu, Y., Ohishi, T. & Tsuruo, T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell 7, 25–37 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Nakamura, H. et al. Genomic spectra of biliary tract cancer. Nat. Genet. 47, 1003–1010 (2015).

    Article  CAS  PubMed  Google Scholar 

  181. Wang, A. et al. Whole-exome sequencing reveals the origin and evolution of hepato-cholangiocarcinoma. Nat. Commun. 9, 894 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Lee, H. W. et al. Clinicopathological characteristics of TERT promoter mutation and telomere length in hepatocellular carcinoma. Medicine (Baltimore) 96, e5766 (2017).

    Article  CAS  Google Scholar 

  183. Oya, H. et al. Comparison between human-telomerase reverse transcriptase mRNA and alpha-fetoprotein mRNA as a predictive value for recurrence of hepatocellular carcinoma in living donor liver transplantation. Transplant. Proc. 38, 3636–3639 (2006).

    Article  CAS  PubMed  Google Scholar 

  184. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02598661 (2019).

  185. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01731951 (2018).

  186. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02426086 (2019).

  187. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02301754 (2019).

  188. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02293707 (2018).

  189. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01197625 (2018).

  190. Khoury, H. J. et al. Immune responses and long-term disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia. Cancer 123, 3061–3072 (2017).

    Article  CAS  PubMed  Google Scholar 

  191. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01660529 (2016).

  192. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00834665 (2019).

  193. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03491683 (2019).

  194. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03502785 (2019).

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Acknowledgements

This work was supported by Institut National du Cancer (INCa) with the International Cancer Genome Consortium (ICGC LICA-FR project) and NoFLIC projects (PAIR HCC, INCa and ARC), INSERM with the “Cancer et Environnement” (plan Cancer), MUTHEC projects (INCa), TELOTHEP project (PRTK2017 INCA) and HETCOLI projects (Tumor Heterogeneity and Ecosystem Program). The group is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology (investissement d’avenir), Coup d’Elan de la Fondation Bettencourt-Shueller, the SIRIC CARPEM, Fondation Mérieux, Prix Duquesne (Ligue Contre le Cancer, Comité de Paris) and Prix Raymond Rosen (Fondation pour la Recherche Médicale).

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Nault, JC., Ningarhari, M., Rebouissou, S. et al. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat Rev Gastroenterol Hepatol 16, 544–558 (2019). https://doi.org/10.1038/s41575-019-0165-3

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