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// Tareq A. Juratli 1, 2 , Christian Thiede 3 , Mara V.A. Koerner 1 , Shilpa S. Tummala 1 , Dirk Daubner 4 , Ganesh M. Shankar 1 , Erik A. Williams 5 , Maria Martinez-Lage 5 , Silke Soucek 2 , Katja Robel 2 , Tristan Penson 1 , Mechthild Krause 6, 7, 8 , Steffen Appold 6, 7, 8 , Matthias Meinhardt 9 , Thomas Pinzer 2 , Julie J. Miller 10 , Dietmar Krex 2, 7 , Heather A. Ely 11 , Ian M. Silverman 11 , Jason Christiansen 11 , Gabriele Schackert 2, 7 , Hiroaki Wakimoto 1 , Matthias Kirsch 2, 7, * , Priscilla K. Brastianos 12, * and Daniel P. Cahill 1, * 1 Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA 2 Department of Neurosurgery, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 3 Department of Medicine I, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 4 Institute of Neuroradiology, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 5 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA 6 Institute of Radiooncology, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany 7 German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Department of Radiation Oncology and OncoRay, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 9 Institute of Pathology, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 10 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA 11 Ignyta, Inc., San Diego, California, USA 12 Department of Medicine, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA * These authors have contributed equally to this work Correspondence to: Daniel P. Cahill, email: cahill@mgh.harvard.edu Priscilla K. Brastianos, email: PBRASTIANOS@mgh.harvard.edu Matthias Kirsch, email: Matthias.kirsch@uniklinikum-dresden.de Keywords: meningioma; telomere; heterogeneity; rearrangements; fusion Received: August 18, 2017 Accepted: October 30, 2017 Published: November 24, 2017 ABSTRACT Background: Recent studies have reported mutations in the telomerase reverse transcriptase promoter ( TERT p) 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 TERT p and ATRX/DAXX mutations, and TERT rearrangements. Additionally, TERT p 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 TERT p mutations were detected in six patients (6/26 = 23%). Regional intratumoral heterogeneity in TERT p mutation status was noted. In 4 patients, TERT p 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, TERT p mutation was detected in two patients (10.5%). Importantly, we found that patients with emergence of TERT p mutations had a substantially shorter OS than their TERT p 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, TERT p 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 TERT p mutation status, consistent with this model of late emergence in tumor evolution. Thus, early detection of TERT p mutations may define patients with more aggressive meningiomas. Stratification for TERT alterations should be adopted in future clinical trials of progressive/higher-grade meningiomas.