Advertisement

Acta Neuropathologica

, Volume 126, Issue 6, pp 931–937 | Cite as

TERT promoter mutations in primary and secondary glioblastomas

  • Naosuke Nonoguchi
  • Takashi Ohta
  • Ji-Eun Oh
  • Young-Ho Kim
  • Paul Kleihues
  • Hiroko OhgakiEmail author
Original Paper

Abstract

Telomerase reverse transcriptase (TERT) is up-regulated in a variety of human neoplasms. Mutations in the core promoter region of the TERT gene, which increases promoter activity, have been reported in melanomas and a variety of human neoplasms, including gliomas. In the present study, we screened for TERT promoter mutations by direct DNA sequencing in a population-based collection of 358 glioblastomas. TERT promoter mutations (C228T, C250T) were detected in 55 % glioblastomas analysed. Of these, 73 % had a C228T mutation, and 27 % had a C250T mutation; only one glioblastoma had both C228T and C250T mutations. TERT promoter mutations were significantly more frequent in primary (IDH1 wild-type) glioblastomas (187/322; 58 %) than in secondary (IDH1 mutated) glioblastomas (10/36, 28 %; P = 0.0056). They showed significant inverse correlations with IDH1 mutations (P = 0.0056) and TP53 mutations (P = 0.043), and a significant positive correlation with EGFR amplification (P = 0.048). Glioblastoma patients with TERT mutations showed a shorter survival than those without TERT mutations in univariate analysis (median, 9.3 vs. 10.5 months; P = 0.015) and multivariate analysis after adjusting for age and gender (HR 1.38, 95 % CI 1.01–1.88, P = 0.041). However, TERT mutations had no significant impact on patients’ survival in multivariate analysis after further adjusting for other genetic alterations, or when primary and secondary glioblastomas were separately analysed. These results suggest that the prognostic value of TERT mutations for poor survival is largely due to their inverse correlation with IDH1 mutations, which are a significant prognostic marker of better survival in patients with secondary glioblastomas.

Keywords

TERT promoter mutations IDH1 mutations Primary glioblastomas Secondary glioblastomas 

Supplementary material

401_2013_1163_MOESM1_ESM.ppt (1.1 mb)
Supplementary Fig. 1. Relationship between TERT promoter mutations, IDH1 mutations and 1p/19q co-deletion in all glioblastomas, primary glioblastomas, and secondary glioblastomas. Data are based on 200 cases for which all the data on TERT promoter mutations, IDH1 mutations and 1p/19q co-deletion are available. Supplementary Fig. 2. Multivariate analysis after adjusting for age, gender, and genetic alterations, showing that TERT promoter mutations are not prognostic for poor survival in glioblastomas. (PPT 1177 kb)
401_2013_1163_MOESM2_ESM.docx (20 kb)
Supplementary material (DOCX 20 kb)

References

  1. 1.
    Arita H, Narita Y, Fukushima S, Tateishi K, Matsushita Y, Yoshida A, Miyakita Y, Ohno M, Collins VP, Kawahara N, Shibui S, Ichimura K (2013) Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 126:267–276PubMedCrossRefGoogle Scholar
  2. 2.
    Blackburn EH, Greider CW, Henderson E, Lee MS, Shampay J, Shippen-Lentz D (1989) Recognition and elongation of telomeres by telomerase. Genome 31(2):553–560PubMedCrossRefGoogle Scholar
  3. 3.
    Bleeker FE, Atai NA, Lamba S, Jonker A, Rijkeboer D, Bosch KS, Tigchelaar W, Troost D, Vandertop WP, Bardelli A, Van Noorden CJ (2010) The prognostic IDH1(R132) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol 119(4):487–494PubMedCrossRefGoogle Scholar
  4. 4.
    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(6):1555–1560PubMedGoogle Scholar
  5. 5.
    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404PubMedCrossRefGoogle Scholar
  6. 6.
    Counter CM, Meyerson M, Eaton EN, Ellisen LW, Caddle SD, Haber DA, Weinberg RA (1998) Telomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase. Oncogene 16(9):1217–1222PubMedCrossRefGoogle Scholar
  7. 7.
    DeMasters BK, Markham N, Lillehei KO, Shroyer KR (1997) Differential telomerase expression in human primary intracranial tumors. Am J Clin Pathol 107(5):548–554PubMedGoogle Scholar
  8. 8.
    Farre D, Roset R, Huerta M, Adsuara JE, Rosello L, Alba MM, Messeguer X (2003) Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res 31(13):3651–3653PubMedCrossRefGoogle Scholar
  9. 9.
    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):l1CrossRefGoogle Scholar
  10. 10.
    Greider CW, Blackburn EH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337(6205):331–337PubMedCrossRefGoogle Scholar
  11. 11.
    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(10):2117–2125PubMedGoogle Scholar
  12. 12.
    Homma T, Fukushima T, Vaccarella S, Yonekawa Y, Di Patre PL, Franceschi S, Ohgaki H (2006) Correlation among pathology, genotype, and patient outcomes in glioblastoma. J Neuropathol Exp Neurol 65:846–854PubMedCrossRefGoogle Scholar
  13. 13.
    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(6122):959–961PubMedCrossRefGoogle Scholar
  14. 14.
    Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, Paris S, Boisselier B, Idbaih A, Laigle-Donadey F, Hoang-Xuan K, Sanson M, Delattre JY (2010) IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75(17):1560–1566PubMedCrossRefGoogle Scholar
  15. 15.
    Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339(6122):957–959PubMedCrossRefGoogle Scholar
  16. 16.
    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 I, 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(15):6021–6026PubMedCrossRefGoogle Scholar
  17. 17.
    Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266(5193):2011–2015PubMedCrossRefGoogle Scholar
  18. 18.
    La Torre D, Conti A, Aguennouz MH, De Pasquale MG, Romeo S, Angileri FF, Cardali S, Tomasello C, Alafaci C, Germano A (2013) Telomere length modulation in human astroglial brain tumors. PLoS ONE 8(5):e64296PubMedCrossRefGoogle Scholar
  19. 19.
    Langford LA, Piatyszek MA, Xu R, Schold SC Jr, Shay JW (1995) Telomerase activity in human brain tumours. Lancet 346(8985):1267–1268PubMedCrossRefGoogle Scholar
  20. 20.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) (2007) WHO classification of tumours of the central nervous system. IARC, LyonGoogle Scholar
  21. 21.
    Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM (2002) PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics 18(2):333–334PubMedCrossRefGoogle Scholar
  22. 22.
    Nobusawa S, Lachuer J, Wierinckx A, Kim YH, Huang J, Legras C, Kleihues P, Ohgaki H (2010) Intratumoral patterns of genomic imbalance in glioblastomas. Brain Pathol 20(5):936–944PubMedGoogle Scholar
  23. 23.
    Nobusawa S, Watanabe T, Kleihues P, Ohgaki H (2009) IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res 15(19):6002–6007PubMedCrossRefGoogle Scholar
  24. 24.
    Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lutolf UM, Kleihues P (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64(19):6892–6899PubMedCrossRefGoogle Scholar
  25. 25.
    Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170(5):1445–1453PubMedCrossRefGoogle Scholar
  26. 26.
    Ohgaki H, Kleihues P (2013) The definition of primary and secondary glioblastoma. Clin Cancer Res 19(4):764–772PubMedCrossRefGoogle Scholar
  27. 27.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Naosuke Nonoguchi
    • 1
    • 2
  • Takashi Ohta
    • 1
  • Ji-Eun Oh
    • 1
  • Young-Ho Kim
    • 1
    • 3
  • Paul Kleihues
    • 4
  • Hiroko Ohgaki
    • 1
    Email author
  1. 1.Section of Molecular PathologyInternational Agency for Research on CancerLyonFrance
  2. 2.Department of NeurosurgeryOsaka Medical CollegeTakatsukiJapan
  3. 3.Translational Epidemiology Research BranchNational Cancer CenterGoyangKorea
  4. 4.Medical FacultyUniversity of ZurichZurichSwitzerland

Personalised recommendations