Skip to main content

Advertisement

SpringerLink
Log in

hTERT promoter methylation in meningiomas and central nervous hemangiopericytomas

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

In meningiomas, prognostic impact of mutations in the human telomerase reverse transcriptase (hTERT) promoter region was recently shown, while studies of promoter methylation and analyses of hemangiopericytomas are lacking. hTERT promoter methylation was analyzed in 78 meningioma and 38 meningeal hemangiopericytoma samples by methylation-specific polymerase chain reaction (MS-PCR) and compared with histopathological and clinical variables and with immunohistochemical hTERT expression. Promoter methylation was found in 62 samples (53 %) and tended to be higher in meningiomas (N = 19/41, 46 %) than in hemangiopericytomas (N = 8/33, 24 %, p = .057). In meningiomas, methylation was 16, 60 and 77 % in grade I, II and III tumors (p < .001) and higher in recurrent (N = 33/37, 89 %) than in primary diagnosed (N = 19/41, 46 %) tumors (OR 5.14, 95 % CI 1.34–19.71, p = .017). Univariate analyses showed shorter mean progression free and overall survival in methylated than in unmethylated individuals (26 vs. 100 months; p = .045 and 110 vs. 113 months; p = .025, respectively). Moreover, hTERT expression was found in 70 % (N = 53) and was more frequent in methylated than in unmethylated samples (78 vs. 52 %, OR 3.36, 95 % CI 1.20–9.40, p = .021). In hemangiopericytomas, methylation was similar in grade II (24 %) and III (25 %, p > .05) and in primary (24 %) and recurrent tumors (40 %, p > .05). hTERT expression was similar as compared to meningiomas (74 %, N = 28, p > .05) but was independent of promoter methylation (OR 4.26, 95 % CI 0.47–39.0, p = .199). In meningeal tumors, hTERT promoter methylation is more common than mutations and in meningiomas but not in hemangiopericytomas positively correlated with WHO grade and hTERT expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kalala JP, Maes L, Vandenbroecke C, de Ridder L (2005) The hTERT protein as a marker for malignancy in meningiomas. Oncol Rep 13:273–277

    CAS  PubMed  Google Scholar 

  2. Maes L, Kalala JP, Cornelissen R, de Ridder L (2006) Telomerase activity and hTERT protein expression in meningiomas: an analysis in vivo versus in vitro. Anticancer Res 26:2295–2300

    CAS  PubMed  Google Scholar 

  3. Maes L, Lippens E, Kalala JP, de Ridder L (2005) The hTERT-protein and Ki-67 labelling index in recurrent and non-recurrent meningiomas. Cell Prolif 38:3–12. doi:10.1111/j.1365-2184.2005.00325.x

    Article  CAS  PubMed  Google Scholar 

  4. Simon M, Park TW, Leuenroth S, Hans VH, Loning T, Schramm J (2000) Telomerase activity and expression of the telomerase catalytic subunit, hTERT, in meningioma progression. J Neurosurg 92:832–840. doi:10.3171/jns.2000.92.5.0832

    Article  CAS  PubMed  Google Scholar 

  5. 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 126:267–276. doi:10.1007/s00401-013-1141-6

    Article  CAS  PubMed  Google Scholar 

  6. Arita H, Narita Y, Takami H, Fukushima S, Matsushita Y, Yoshida A, Miyakita Y, Ohno M, Shibui S, Ichimura K (2013) TERT promoter mutations rather than methylation are the main mechanism for TERT upregulation in adult gliomas. Acta Neuropathol 126:939–941. doi:10.1007/s00401-013-1203-9

    Article  PubMed  Google Scholar 

  7. 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 Ie M, 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. doi:10.1073/pnas.1303607110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tabori U, Ma J, Carter M, Zielenska M, Rutka J, Bouffet E, Bartels U, Malkin D, Hawkins C (2006) Human telomere reverse transcriptase expression predicts progression and survival in pediatric intracranial ependymoma. J Clin Oncol 24:1522–1528. doi:10.1200/JCO.2005.04.2127

    Article  CAS  PubMed  Google Scholar 

  9. Koelsche C, Sahm F, Capper D, Reuss D, Sturm D, Jones DT, Kool M, Northcott PA, Wiestler B, Bohmer K, Meyer J, Mawrin C, Hartmann C, Mittelbronn M, Platten M, Brokinkel B, Seiz M, Herold-Mende C, Unterberg A, Schittenhelm J, Weller M, Pfister S, Wick W, Korshunov A, von Deimling A (2013) Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathol 126:907–915. doi:10.1007/s00401-013-1195-5

    Article  CAS  PubMed  Google Scholar 

  10. Park CK, Lee SH, Kim JY, Kim JE, Kim TM, Lee ST, Choi SH, Park SH, Kim IH (2014) Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma. Oncotarget 5:3399–3407

    Article  PubMed  PubMed Central  Google Scholar 

  11. Huang DS, Wang Z, He XJ, Diplas BH, Yang R, Killela PJ, Meng Q, Ye ZY, Wang W, Jiang XT, Xu L, He XL, Zhao ZS, Xu WJ, Wang HJ, Ma YY, Xia YJ, Li L, Zhang RX, Jin T, Zhao ZK, Xu J, Yu S, Wu F, Liang J, Wang S, Jiao Y, Yan H, Tao HQ (2015) 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. doi:10.1016/j.ejca.2015.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Goutagny S, Nault JC, Mallet M, Henin D, Rossi JZ, Kalamarides M (2014) High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol 24:184–189. doi:10.1111/bpa.12110

    Article  CAS  PubMed  Google Scholar 

  13. Sahm F, Schrimpf D, Olar A, Koelsche C, Reuss D, Bissel J, Kratz A, Capper D, Schefzyk S, Hielscher T, Wang Q, Sulman EP, Adeberg S, Koch A, Okuducu AF, Brehmer S, Schittenhelm J, Becker A, Brokinkel B, Schmidt M, Ull T, Gousias K, Friederike A, Lamszus KK, Debus J, Mawrin C, Kim YJ, Simon M, Ketter R, Paulus W, Aldape KD, Herold-Mende C, von Deimling A (2016) TERT promoter mutations and risk of recurrence in meningioma. J Natl Cancer Inst 108. doi:10.1093/jnci/djv377

  14. Castelo-Branco P, Choufani S, Mack S, Gallagher D, Zhang C, Lipman T, Zhukova N, Walker EJ, Martin D, Merino D, Wasserman JD, Elizabeth C, Alon N, Zhang L, Hovestadt V, Kool M, Jones DT, Zadeh G, Croul S, Hawkins C, Hitzler J, Wang JC, Baruchel S, Dirks PB, Malkin D, Pfister S, Taylor MD, Weksberg R, Tabori U (2013) Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study. Lancet Oncol 14:534–542. doi:10.1016/S1470-2045(13)70110-4

    Article  CAS  PubMed  Google Scholar 

  15. Ruland V, Hartung S, Kordes U, Wolff JE, Paulus W, Hasselblatt M (2014) Methylation of the hTERT promoter is frequent in choroid plexus tumors but not of independent prognostic value. J Neurooncol 119:215–216. doi:10.1007/s11060-014-1473-7

    Article  PubMed  Google Scholar 

  16. Kochling M, Ewelt C, Furtjes G, Peetz-Dienhart S, Koos B, Hasselblatt M, Paulus W, Stummer W, Brokinkel B (2016) hTERT promoter methylation in pituitary adenomas. Brain Tumor Pathol 33:27–34. doi:10.1007/s10014-015-0230-8

    Article  PubMed  Google Scholar 

  17. Perry A, Louis DN, Scheithauer BW, Budka H, von Deimling A (2007) Meningiomas. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) WHO classification of tumors of the central nervous system, 4 edn. International agency on cancer research, Lyon, pp 164–172

  18. Paulus W, Scheithauer BW, Perry A (2007) Mesenchymal, non-meningothelial tumours. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) WHO Classification of tumors of the central nervous System, 4 edn. International agency on cancer research, Lyon, pp 173–177

  19. Maes L, Kalala JP, Cornelissen M, de Ridder L (2007) Progression of astrocytomas and meningiomas: an evaluation in vitro. Cell Prolif 40:14–23. doi:10.1111/j.1365-2184.2007.00415.x

    Article  CAS  PubMed  Google Scholar 

  20. Boldrini L, Pistolesi S, Gisfredi S, Ursino S, Lupi G, Caniglia M, Pingitore R, Basolo F, Parenti G, Fontanini G (2003) Telomerase in intracranial meningiomas. Int J Mol Med 12:943–947

    CAS  PubMed  Google Scholar 

  21. Maes L, Van Neste L, Van Damme K, Kalala JP, De Ridder L, Bekaert S, Cornelissen M (2007) Relation between telomerase activity, hTERT and telomere length for intracranial tumours. Oncol Rep 18:1571–1576

    CAS  PubMed  Google Scholar 

  22. Chen HJ, Liang CL, Lu K, Lin JW, Cho CL (2000) Implication of telomerase activity and alternations of telomere length in the histologic characteristics of intracranial meningiomas. Cancer 89:2092–2098

    Article  CAS  PubMed  Google Scholar 

  23. Leuraud P, Dezamis E, Aguirre-Cruz L, Taillibert S, Lejeune J, Robin E, Mokhtari K, Boch AL, Cornu P, Delattre JY, Sanson M (2004) Prognostic value of allelic losses and telomerase activity in meningiomas. J Neurosurg 100:303–309. doi:10.3171/jns.2004.100.2.0303

    Article  CAS  PubMed  Google Scholar 

  24. Langford LA, Piatyszek MA, Xu R, Schold SC Jr, Wright WE, Shay JW (1997) Telomerase activity in ordinary meningiomas predicts poor outcome. Hum Pathol 28:416–420

    Article  CAS  PubMed  Google Scholar 

  25. Simon M, Park TW, Koster G, Mahlberg R, Hackenbroch M, Bostrom J, Loning T, Schramm J (2001) Alterations of INK4a(p16-p14ARF)/INK4b(p15) expression and telomerase activation in meningioma progression. J Neurooncol 55:149–158

    Article  CAS  PubMed  Google Scholar 

  26. Cai J, Yang P, Zhang C, Zhang W, Liu Y, Bao Z, Liu X, Du W, Wang H, Jiang T, Jiang C (2014) ATRX mRNA expression combined with IDH1/2 mutational status and Ki-67 expression refines the molecular classification of astrocytic tumors: evidence from the whole transcriptome sequencing of 169 samples samples. Oncotarget 5:2551–2561

    Article  PubMed  PubMed Central  Google Scholar 

  27. Dorris K, Sobo M, Onar-Thomas A, Panditharatna E, Stevenson CB, Gardner SL, Dewire MD, Pierson CR, Olshefski R, Rempel SA, Goldman S, Miles L, Fouladi M, Drissi R (2014) Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas. J Neurooncol 117:67–76. doi:10.1007/s11060-014-1374-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nguyen DN, Heaphy CM, de Wilde RF, Orr BA, Odia Y, Eberhart CG, Meeker AK, Rodriguez FJ (2013) Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas. Brain Pathol 23:237–243. doi:10.1111/j.1750-3639.2012.00630.x

    Article  PubMed  Google Scholar 

  29. Wiestler B, Capper D, Holland-Letz T, Korshunov A, von Deimling A, Pfister SM, Platten M, Weller M, Wick W (2013) ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol 126:443–451. doi:10.1007/s00401-013-1156-z

    Article  CAS  PubMed  Google Scholar 

  30. Estey EH (2013) Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia. Leukemia 27:1803–1812. doi:10.1038/leu.2013.173

    Article  CAS  PubMed  Google Scholar 

  31. Pettigrew KA, Armstrong RN, Colyer HA, Zhang SD, Rea IM, Jones RE, Baird DM, Mills KI (2012) Differential TERT promoter methylation and response to 5-aza-2′-deoxycytidine in acute myeloid leukemia cell lines: TERT expression, telomerase activity, telomere length, and cell death. Genes Chromosomes Cancer 51:768–780. doi:10.1002/gcc.21962

    Article  CAS  PubMed  Google Scholar 

  32. Zhang X, Li B, de Jonge N, Bjorkholm M, Xu D (2015) The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression. Oncotarget 6:4888–4900. doi:10.18632/oncotarget.2917

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hajek M, Votruba I, Holy A, Krecmerova M, Tloust’ova E (2008) Alpha anomer of 5-aza-2′-deoxycytidine down-regulates hTERT mRNA expression in human leukemia HL-60 cells. Biochem Pharmacol 75:965–972. doi:10.1016/j.bcp.2007.10.018

    Article  CAS  PubMed  Google Scholar 

  34. Grandjenette C, Schnekenburger M, Karius T, Ghelfi J, Gaigneaux A, Henry E, Dicato M, Diederich M (2014) 5-aza-2′-deoxycytidine-mediated c-myc down-regulation triggers telomere-dependent senescence by regulating human telomerase reverse transcriptase in chronic myeloid leukemia. Neoplasia 16:511–528. doi:10.1016/j.neo.2014.05.009

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wu YL, Dudognon C, Nguyen E, Hillion J, Pendino F, Tarkanyi I, Aradi J, Lanotte M, Tong JH, Chen GQ, Segal-Bendirdjian E (2006) Immunodetection of human telomerase reverse-transcriptase (hTERT) re-appraised: nucleolin and telomerase cross paths. J Cell Sci 119:2797–2806

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work received funding by the German Society of Neurosurgery (Stiftung Neurochirurgische Forschung der Deutschen Gesellschaft für Neurochirurgie). The funder was not involved in design of the study, laboratory research and analysis of the results. We also cordially thank Björn Koos for the support of the laboratory research. There are no financial or intellectual conflicts of interest.

Funding

This study (recipient BB) was funded by the German Society of Neurosurgery (Stiftung Neurochirurgische Forschung der Deutschen Gesellschaft für Neurochirurgie).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany

    Gina Fürtjes, Michaela Köchling, Walter Stummer & Benjamin Brokinkel

  2. Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany

    Susanne Peetz-Dienhart, Andrea Wagner, Katharina Heß, Martin Hasselblatt, Volker Senner & Werner Paulus

Authors
  1. Gina Fürtjes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michaela Köchling
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susanne Peetz-Dienhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katharina Heß
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin Hasselblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Volker Senner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Walter Stummer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Werner Paulus
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Benjamin Brokinkel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin Brokinkel.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This is a retrospective, non-interventional study. Data collection and scientific use was approved by the local ethics committee and permitted by the patients in each single case (Muenster 2007-420-f-S). This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fürtjes, G., Köchling, M., Peetz-Dienhart, S. et al. hTERT promoter methylation in meningiomas and central nervous hemangiopericytomas. J Neurooncol 130, 79–87 (2016). https://doi.org/10.1007/s11060-016-2226-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-016-2226-6

Keywords

Search

Navigation