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Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss

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Abstract

Telomere lengthening is one of the key events in most cancers, and depends largely on telomerase activation. Telomerase activation is a well-known phenomenon in gliomas; however, its mechanism remains obscure. In this study, we investigated the presence of mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in a series of 546 gliomas. We found a high incidence of mutually exclusive mutations located at two hot spots, C228T and C250T, in all subtypes of gliomas (55 %). The frequency of mutation was particularly high among primary glioblastomas (70 %) and pure oligodendroglial tumors (74 %), while relatively low in diffuse astrocytomas and anaplastic astrocytomas (19 and 25 %, respectively). The expression level of TERT in tumors carrying those mutations was on average 6.1 times higher than that of wild-type tumors, indicating that the mutated promoter leads to upregulation of TERT. TERT promoter mutations were observed in almost all tumors harboring concurrent total 1p19q loss and IDH1/2 mutations (98 %). Otherwise TERT promoter mutations were mostly observed among IDH wild-type tumors. Most EGFR amplifications (92 %) were also associated with TERT promoter mutations. Our data indicate that mutation of the TERT promoter is one of the major mechanisms of telomerase activation in gliomas. The unique pattern of TERT promoter mutations in relation to other genetic alterations suggests that they play distinct roles in the pathogenesis of oligodendroglial and astrocytic tumors. Our results shed a new light on the role of telomerase activation in the development of adult gliomas.

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References

  1. Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, Rodriguez FJ, Cahill DP, McLendon R, Riggins G, Velculescu VE, Oba-Shinjo SM, Marie SK, Vogelstein B, Bigner D, Yan H, Papadopoulos N, Kinzler KW (2011) Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333:1453–1455

    Article  PubMed  CAS  Google Scholar 

  2. Boldrini L, Pistolesi S, Gisfredi S, Ursino S, Ali G, Pieracci N, Basolo F, Parenti G, Fontanini G (2006) Telomerase activity and hTERT mRNA expression in glial tumors. Int J Oncol 28:1555–1560

    PubMed  CAS  Google Scholar 

  3. Conomos D, Pickett HA, Reddel RR (2013) Alternative lengthening of telomeres: remodeling the telomere architecture. Front Oncol 3:27

    Article  PubMed  Google Scholar 

  4. Dome JS, Chung S, Bergemann T, Umbricht CB, Saji M, Carey LA, Grundy PE, Perlman EJ, Breslow NE, Sukumar S (1999) High telomerase reverse transcriptase (hTERT) messenger RNA level correlates with tumor recurrence in patients with favorable histology Wilms’ tumor. Cancer Res 59:4301–4307

    PubMed  CAS  Google Scholar 

  5. Fukushima T, Yoshino A, Katayama Y, Watanabe T, Kusama K, Moro I (2002) Prediction of clinical course of diffusely infiltrating astrocytomas from telomerase expression and quantitated activity level. Cancer Lett 187:191–198

    Article  PubMed  CAS  Google Scholar 

  6. Hakin-Smith V, Jellinek DA, Levy D, Carroll T, Teo M, Timperley WR, McKay MJ, Reddel RR, Royds JA (2003) Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet 361:836–838

    Article  PubMed  CAS  Google Scholar 

  7. Heaphy CM, Subhawong AP, Hong SM, Goggins MG, Montgomery EA, Gabrielson E, Netto GJ, Epstein JI, Lotan TL, Westra WH, Shih Ie M, Iacobuzio-Donahue CA, Maitra A, Li QK, Eberhart CG, Taube JM, Rakheja D, Kurman RJ, Wu TC, Roden RB, Argani P, De Marzo AM, Terracciano L, Torbenson M, Meeker AK (2011) Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol 179:1608–1615

    Article  PubMed  CAS  Google Scholar 

  8. Henson JD, Hannay JA, McCarthy SW, Royds JA, Yeager TR, Robinson RA, Wharton SB, Jellinek DA, Arbuckle SM, Yoo J, Robinson BG, Learoyd DL, Stalley PD, Bonar SF, Yu D, Pollock RE, Reddel RR (2005) A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas. Clin Cancer Res 11:217–225

    PubMed  CAS  Google Scholar 

  9. Hiraga S, Ohnishi T, Izumoto S, Miyahara E, Kanemura Y, Matsumura H, Arita N (1998) Telomerase activity and alterations in telomere length in human brain tumors. Cancer Res 58:2117–2125

    PubMed  CAS  Google Scholar 

  10. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, Schadendorf D, Kumar R (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339:959–961

    Article  PubMed  CAS  Google Scholar 

  11. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–959

    Article  PubMed  CAS  Google Scholar 

  12. Ichimura K (2012) Molecular pathogenesis of IDH mutations in gliomas. Brain Tumor Pathol 29:131–139

    Article  PubMed  CAS  Google Scholar 

  13. Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A, Collins VP (2000) Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res 60:417–424

    PubMed  CAS  Google Scholar 

  14. Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, Collins VP (2009) IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol 11:341–347

    Article  PubMed  CAS  Google Scholar 

  15. Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde RF, Rodriguez FJ, Rosemberg S, Oba-Shinjo SM, Nagahashi Marie SK, Bettegowda C, Agrawal N, Lipp E, Pirozzi C, Lopez G, He Y, Friedman H, Friedman AH, Riggins GJ, Holdhoff M, Burger P, McLendon R, Bigner DD, Vogelstein B, Meeker AK, Kinzler KW, Papadopoulos N, Diaz LA, Yan H (2012) Frequent ATRX, CIC, and FUBP1 mutations refine the classification of malignant gliomas. Oncotarget 3:709–722

    PubMed  Google Scholar 

  16. Kannan K, Inagaki A, Silber J, Gorovets D, Zhang J, Kastenhuber ER, Heguy A, Petrini JH, Chan TA, Huse JT (2012) Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. Oncotarget 3:1194–1203

    PubMed  Google Scholar 

  17. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih IM, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H (2013) 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 USA 110:6021–6026

    Article  PubMed  CAS  Google Scholar 

  18. Langford LA, Piatyszek MA, Xu R, Schold SC Jr, Shay JW (1995) Telomerase activity in human brain tumours. Lancet 346:1267–1268

    Article  PubMed  CAS  Google Scholar 

  19. Le S, Zhu JJ, Anthony DC, Greider CW, Black PM (1998) Telomerase activity in human gliomas. Neurosurgery 42:1120–1124

    Article  PubMed  CAS  Google Scholar 

  20. Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA, Fontebasso AM, Fleming A, Hadjadj D, Schwartzentruber J, Majewski J, Dong Z, Siegel P, Albrecht S, Croul S, Jones DT, Kool M, Tonjes M, Reifenberger G, Faury D, Zadeh G, Pfister S, Jabado N (2012) Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol 124:615–625

    Article  PubMed  CAS  Google Scholar 

  21. Lotsch D, Ghanim B, Laaber M, Wurm G, Weis S, Lenz S, Webersinke G, Pichler J, Berger W, Spiegl-Kreinecker S (2013) Prognostic significance of telomerase-associated parameters in glioblastoma: effect of patient age. Neuro Oncol 15:423–432

    Article  PubMed  Google Scholar 

  22. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

    Article  PubMed  Google Scholar 

  23. Maida Y, Yasukawa M, Furuuchi M, Lassmann T, Possemato R, Okamoto N, Kasim V, Hayashizaki Y, Hahn WC, Masutomi K (2009) An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature 461:230–235

    Article  PubMed  CAS  Google Scholar 

  24. Masutomi K, Hahn WC (2003) Telomerase and tumorigenesis. Cancer Lett 194:163–172

    Article  PubMed  CAS  Google Scholar 

  25. McCabe MG, Ichimura K, Liu L, Plant K, Backlund LM, Pearson DM, Collins VP (2006) High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors. J Neuropathol Exp Neurol 65:549–561

    Article  PubMed  CAS  Google Scholar 

  26. Mulholland S, Pearson DM, Hamoudi RA, Malley DS, Smith CM, Weaver JM, Jones DT, Kocialkowski S, Backlund LM, Collins VP, Ichimura K (2012) MGMT CpG island is invariably methylated in adult astrocytic and oligodendroglial tumors with IDH1 or IDH2 mutations. Int J Cancer 131:1104–1113

    Article  PubMed  CAS  Google Scholar 

  27. Nguyen DN, Heaphy CM, de Wilde RF, Orr BA, Odia Y, Eberhart CG, Meeker AK, Rodriguez FJ (2012) Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas. Brain Pathol 23:237–243

    Article  PubMed  Google Scholar 

  28. Okita Y, Narita Y, Miyakita Y, Ohno M, Matsushita Y, Fukushima S, Sumi M, Ichimura K, Kayama T, Shibui S (2012) IDH1/2 mutation is a prognostic marker for survival and predicts response to chemotherapy for grade II gliomas concomitantly treated with radiation therapy. Int J Oncol [Epub ahead of print]

  29. Ruden M, Puri N (2012) Novel anticancer therapeutics targeting telomerase. Cancer Treat Rev 39:444–456

    Article  PubMed  Google Scholar 

  30. Sahm F, Koelsche C, Meyer J, Pusch S, Lindenberg K, Mueller W, Herold-Mende C, von Deimling A, Hartmann C (2012) CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta Neuropathol 123:853–860

    Article  PubMed  CAS  Google Scholar 

  31. Sano T, Asai A, Mishima K, Fujimaki T, Kirino T (1998) Telomerase activity in 144 brain tumours. Br J Cancer 77:1633–1637

    Article  PubMed  CAS  Google Scholar 

  32. Schmidt EE, Ichimura K, Goike HM, Moshref A, Liu L, Collins VP (1999) Mutational profile of the PTEN gene in primary human astrocytic tumors and cultivated xenografts. J Neuropathol Exp Neurol 58:1170–1183

    Article  PubMed  CAS  Google Scholar 

  33. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jager N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Fruhwald MC, Roggendorf W, Kramm C, Durken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231

    Article  PubMed  CAS  Google Scholar 

  34. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  35. TCGA (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  Google Scholar 

  36. Yip S, Butterfield YS, Morozova O, Chittaranjan S, Blough MD, An J, Birol I, Chesnelong C, Chiu R, Chuah E, Corbett R, Docking R, Firme M, Hirst M, Jackman S, Karsan A, Li H, Louis DN, Maslova A, Moore R, Moradian A, Mungall KL, Perizzolo M, Qian J, Roldan G, Smith EE, Tamura-Wells J, Thiessen N, Varhol R, Weiss S, Wu W, Young S, Zhao Y, Mungall AJ, Jones SJ, Morin GB, Chan JA, Cairncross JG, Marra MA (2012) Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol 226:7–16

    Article  PubMed  CAS  Google Scholar 

  37. Zeng N, Liu L, McCabe MG, Jones DT, Ichimura K, Collins VP (2009) Real-time quantitative polymerase chain reaction (qPCR) analysis with fluorescence resonance energy transfer (FRET) probes reveals differential expression of the four ERBB4 juxtamembrane region variants between medulloblastoma and pilocytic astrocytoma. Neuropathol Appl Neurobiol 35:353–366

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan [No. 24659650 (H.A.)], and by the National Cancer Center Research and Development Fund [23-A-50 (K.I.)]. The authors thank Dr Danita Pearson for excellent technical assistance and Dr Sylvia Kocialkowski for critical reading of the manuscript.

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Correspondence to Koichi Ichimura.

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401_2013_1141_MOESM3_ESM.pptx

Supplementary Figure 1: Relationships between TERT promoter status and other genetic profiles in the Validation cohort. The Venn diagram shows the relationship between TERT promoter mutation and other genetic profiles in the Validation cohort. a. Relationship between TERT mutations, IDH mutations and TP53 mutations according to the tumor type. b. Relationship between TERT mutations, EGFR amplification and PTEN mutations/homozygous deletions in all pGBM (154) in which alterations of EGFR and/or PTEN predominantly occur. DA, diffuse astrocytoma; AA, anaplastic astrocytoma; pGBM, primary glioblastoma; OL, oligodendroglioma grade II; AO, anaplastic oligodendroglioma; OA, oligoastrocytoma grade II; AOA, anaplastic oligoastrocytoma. None, no alterations in the genes indicated. (PPTX 87 kb)

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Arita, H., Narita, Y., Fukushima, S. et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 126, 267–276 (2013). https://doi.org/10.1007/s00401-013-1141-6

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  • DOI: https://doi.org/10.1007/s00401-013-1141-6

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