Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas
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Tareq A. Juratli1,2, Christian Thiede3, Mara V.A. Koerner1, Shilpa S. Tummala1, Dirk Daubner4, Ganesh M. Shankar1, Erik A. Williams5, Maria Martinez-Lage5, Silke Soucek2, Katja Robel2, Tristan Penson1, Mechthild Krause6,7,8, Steffen Appold6,7,8, Matthias Meinhardt9, Thomas Pinzer2, Julie J. Miller10, Dietmar Krex2,7, Heather A. Ely11, Ian M. Silverman11, Jason Christiansen11, Gabriele Schackert2,7, Hiroaki Wakimoto1, Matthias Kirsch2,7,*, Priscilla K. Brastianos12,* and Daniel P. Cahill1,*
1Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
2Department of Neurosurgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3Department of Medicine I, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
4Institute of Neuroradiology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
5Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
6Institute of Radiooncology, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
7German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
8Department of Radiation Oncology and OncoRay, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
9Institute of Pathology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
10Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
11Ignyta, Inc., San Diego, California, USA
12Department of Medicine, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
*These authors have contributed equally to this work
Daniel P. Cahill, email: [email protected]
Priscilla K. Brastianos, email: [email protected]
Matthias Kirsch, email: [email protected]
Keywords: meningioma; telomere; heterogeneity; rearrangements; fusion
Received: August 18, 2017 Accepted: October 30, 2017 Published: November 24, 2017
Background: 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 for TERTp and ATRX/DAXX mutations, and TERT rearrangements. 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: Somatic TERTp mutations were detected in six patients (6/26 = 23%). Regional intratumoral heterogeneity in TERTp 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, a TERT gene fusion (LPCAT1-TERT) was found in one sample. In contrary, none of the investigated samples harbored an ATRX or DAXX mutation. In the cohort of radiation-induced meningiomas, TERTp mutation was detected in two patients (10.5%). Importantly, we found that patients with emergence of TERTp mutations had a substantially shorter OS than their TERTp 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).
Conclusions: 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 of TERTp mutation status, consistent with this model of late emergence in tumor evolution. Thus, early detection of TERTp mutations may define patients with more aggressive meningiomas. Stratification for TERT alterations should be adopted in future clinical trials of progressive/higher-grade meningiomas.
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