Gui, ChloeWang, JustinPatil, VikasLandry, AlexanderCastelo-Branco, PedroSingh, OliviaTabori, UriAldape, KennethBehling, FelixBarnholtz-Sloan, JillHorbinski, CraigTabatabai, GhazalehAjisebutu, AndrewLiu, JeffPatel, ZeelYakubov, RebecaKaloti, RamneetEllenbogen, YosefWilson, ChristopherCohen-Gadol, AaronTatagiba, MarcosSloan, AndrewHolland, EricChambless, LolaGao, AndrewChotai, SilkyMakarenko, SergeYip, StephenNassiri, FarshadZadeh, Gelareh2025-12-182025-12-182025-11-011522-8517http://hdl.handle.net/10400.1/27984While TERT promoter mutation (TPM) has been es¬tablished as a marker of clinically aggressive meningiomas, this alteration is rare and found in less than 5% of all cases. However, a larger subset of meningiomas may exhibit aberrant TERT expression in the absence of TPMs. This study investigated the effect of TERT gene expression on clinical outcome in meningioma patients. METHODS: Clinical and mo¬lecular data were retrospectively collected on 1241 meningiomas, split into a Toronto discovery cohort and a multi-institutional validation co¬hort. Sanger sequencing and bulk RNA sequencing were used to determine TPM status and TERT gene expression. The effect of TERT expression on progression-free survival (PFS) was assessed using Kaplan-Meier and Cox regression analysis. RESULTS: While meningiomas with TPM showed expectedly higher TERT gene expression compared to wildtype (TP-WT) cases (p<0.0001), TERT expression was still detected in 28.7% (157/547) of TP-WT meningiomas. Meningiomas with TERT expression showed sig¬nificantly worse PFS compared to meningiomas without any TERT expres¬sion. In fact, WHO grade 1 meningiomas with TERT expression had PFS outcomes resembling WHO grade 2 meningiomas lacking TERT expression (p=0.59). In turn, WHO grade 2 meningiomas with TERT expression had clinical outcomes similar to WHO grade 3 meningiomas without TERT ex¬pression (p=0.42). Furthermore, the proportion of meningiomas expressing TERT as well as overall TERT expression levels increased with increasing WHO grade. Multivariable analysis showed that TERT expression was sig-nificantly associated with worse PFS even when controlling for other known predictors of clinical outcome including TPM, CDKN2A/B loss, 1p/22q status and WHO grade (HR 1.85 [95% CI 1.33-2.57], p=0.00024). CON¬CLUSION: TERT expression is a novel independent biomarker of outcome for meningiomas identifiable in up to one-third of cases that may be utilized to reclassify tumors to a higher WHO grade.engjournal article10.1093/neuonc/noaf201.02011523-5866