BACKGROUND: Tumor recurrence after therapy is not infrequent in meningioma, and recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. To date, few are known about the clonal selection toward specific mutations in progressive meningiomas. Here, we determined the TERT promoter mutations in a large series of recurrent progressive meningiomas. METHODS: We screened a cohort of 57 recurrent progressive meningiomas of 24 patients for TERT promoter

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... tions. We further sequenced the TERT promoter in a second cohort consisting of 13 patients with radiation-induced meningiomas. The TERT promoter was amplified using Sanger sequencing performed using ABI Prism 3730 DNA Analyzer. Mutations at the residues at −124 (1295228) and −146 (1295250) bp from the ATG start site in the TERT promoter were scored. RESULTS: Somatic TERT mutations were detected in seven samples from four patients (16.6%) with recurrent meningiomas. Three of four TERT mutations were detected in secondary progressed Grade II to Grade III meningiomas. Intriguingly, two different patients with initially TERT wild-type Grade II meningiomas, who underwent standard therapy with surgery and radiation, then developed a recurrent meningioma with de novo TERT mutation. Conversely, in the cohort of radiation-induced meningiomas, the TERT mutation was detected only in one Grade I meningioma (7.7%). Patients with TERT mutations exhibited a significantly shorter overall survival than patients harboring TERT wild-type meningiomas (3.9 vs 10.9 years, p= 0.008). CONCLUSIONS: We have identified the emergence of TERT promoter mutation in recurrent progressive meningiomas, indicating the presence of ongoing and potentially therapy-related clonal selection impacting the natural history of these tumors. Patients with TERTmutant meningiomas exhibited significantly shorter overall survival than their TERT wild-type counterparts.