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69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

03.06. - 06.06.2018, Münster

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Intratumoral heterogeneity andTERTpromoter mutations in progressive/higher-grade meningiomas

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  • Matthias Kirsch - Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Klinik fuer Neurochirurgie, Dresden, Deutschland
  • Tareq Juratli - Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Klinik fuer Neurochirurgie, Dresden, Deutschland
  • Christian Thiede - Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Medizinische Klinik I, Dresden, Deutschland
  • Shilpa Tummala - Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, Vereinigte Staaten
  • Ganesh Shankar - Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, Vereinigte Staaten
  • Erik Willimas - Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, Vereinigte Staaten
  • Maria Martinez-Lage - Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, Vereinigte Staaten
  • Thomas Pinzer - Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Klinik fuer Neurochirurgie, Dresden, Deutschland
  • Matthias Meinhardt - Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Klinik fuer Neurochirurgie, Dresden, Deutschland
  • Dietmar Krex - Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Klinik fuer Neurochirurgie, Dresden, Deutschland
  • Gabriele Schackert - Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Klinik für Neurochirurgie, Dresden, Deutschland
  • Hiroaki Wakimoto - Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, Vereinigte Staaten
  • Priscilla Brastianos - Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, Vereinigte Staaten
  • Daniel Cahill - Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, Vereinigte Staaten

Deutsche Gesellschaft für Neurochirurgie. 69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie. Münster, 03.-06.06.2018. Düsseldorf: German Medical Science GMS Publishing House; 2018. DocV014

doi: 10.3205/18dgnc015, urn:nbn:de:0183-18dgnc0152

Published: June 18, 2018

© 2018 Kirsch et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

Text

Objective: Recent studies have reported mutations in the telomerase reverse transcriptase promoter (TERTp) in meningiomas. We sought to determine the frequency, clonality and clinical significance of telomere gene alterations in a cohort of patients with progressive/higher-grade meningiomas.

Methods: We characterized 64 temporally- and regionally-distinct specimens from 26 WHO grade III meningioma patients. On initial diagnoses, the meningiomas spanned all WHO grades (3 grade I, 13 grade II and 10 grade III). The tumor samples were screened forTERTp andATRX/DAXXmutations, andTERTrearrangements. Additionally,TERTp was sequenced in a separate cohort of 19 patients with radiation-associated meningiomas. We examined the impact of mutational status on patients’ progression and overall survival.

Results: SomaticTERTp mutations were detected in 6 patients (6/26 = 23%). Regional intratumoral heterogeneity inTERTp mutation status was noted. In 4 patients,TERTp mutations were detected in recurrent specimens but not in the available specimens of the first surgery. Additionally, aTERTgene fusion (LPCAT1-TERT) was found in one sample. In contrary, none of the investigated samples harbored anATRXorDAXXmutation. In the cohort of radiation-induced meningiomas,TERTp mutation was detected in two patients (10.5%). Importantly, we found that patients with emergence ofTERTp mutations had a substantially shorter OS than theirTERTp wild-type counterparts (2.7 years, 95% CI 0.9 – 4.5 years versus 10.8 years, 95% CI 7.8 -12.8 years, p=0.003).

Conclusion: In progressive/higher-grade meningiomas, TERTp mutations are associated with poor survival, supporting a model in which selection of this alteration is a harbinger of aggressive tumor development. In addition, we observe spatial intratumoral heterogeneity ofTERTp mutation status, consistent with this model of late emergence in tumor evolution. Thus, early detection ofTERTp mutations may define patients with more aggressive meningiomas. Stratification forTERTalterations should be adopted in future clinical trials of progressive/higher-grade meningiomas.

Figure 1 [Fig. 1], Figure 2 [Fig. 2]