1052 Impact of TERTp Mutation on Meningioma Outcome is Context-Dependent

INTRODUCTION: TERT-promoter (TERTp) mutation in meningiomas is associated with worse prognosis and is a biomarker of WHO grade 3 meningioma in the 2021 World Health Organization CNS Tumor Classification. METHODS: We analyzed clinical and molecular data of 563 meningiomas from eleven institutions with next-generation TERTp sequencing. Chromosomal copy number (CN) was obtained from microarray or derived from DNA methylation. RESULTS: 55 meningiomas were TERTp-mutant and 508 were TERTp-wildtype (n=27 WHO grade 3). Of TERTp-mutant cases, 51% were men, with a median age of 66 (range 47-85) years. 67.9% (36/53) of TERTp-mutant meningiomas recurred (median 22.2 months, range 0.5-175 months). WHO grade without upgrade for TERTp mutation was determined for 45 TERTp-mutant meningiomas (9 grade 1, 11 grade 2, 25 grade 3). RFS across adjusted grades of TERTp-mutant meningiomas differed significantly (p<0.02). After stratification by adjusted WHO grade, TERTp-mutant and wildtype meningiomas did not differ in RFS. CDKN2A/B locus was lost in 43.8% of TERTp-mutant meningiomas (34.0% homozygous loss, 8.5% hemizygous loss). TERTp-mutant meningiomas with intact CDKN2A/B demonstrated a significantly longer OS and RFS compared with both TERTp-mutant meningiomas with CDKN2A/B loss and TERTp-wildtype grade 3 meningiomas (p<0.03). Nearly all TERTp-mutant meningiomas (91.8%) showed concurrent CN aberrations, with frequent loss of chromosome 1p (77.6%). Only three TERTp-mutant meningiomas had no high-risk CN variations, and none experienced recurrence or death with an average follow-up of 8.1 years. CONCLUSIONS: TERTp mutation rarely occurs in the absence of other molecular markers of aggressive behavior in meningiomas. TERTp-mutant meningiomas without additional molecular signatures of aggressiveness display a more indolent behavior, suggesting that TERTp-mutation is context-dependent in meningiomas.