2025 Proffered Presentations
S252: TERTP MUTANT MENINGIOMAS IN THE ABSENCE OF CONCURRENT AGGRESSIVE FEATURES EXHIBIT BETTER OUTCOMES THAN TERTP WILDTYPE WHO GRADE 3 MENINGIOMAS
Karenna J Groff1; Ruchit V Patel2; William C Chen3; Mark W Youngblood4; Hia S Ghosh2; Catena Kresbach5; Christopher Mount6; Vijay Nitturi7; Marc Rosenblum8; Akshay Save1; Abigail K Suwala9; Tejus A Bale8; Chunyu Cai10; Akash J Patel7; Timothy E Richardson11; Sandro Santagata2; Felix Sahm9; Ulrich Schüller5; Chandra Sen1; Stephen T Magill4; David R Raleigh3; Donato R Pacione1; Matija Snuderl1; Wenya Linda Bi2; 1NYU Langone Health; 2Brigham and Women's Hospital; 3UCSF; 4Northwestern University; 5University Medical Center Hamburg; 6Massachusetts General Hospital; 7Baylor College of Medicine; 8Memorial Sloan Kettering Cancer Center; 9University Hospital Heidelberg; 10UT Southwestern Medical Center; 11Mount Sinai Hospital
Purpose: TERT-promoter (TERTp) mutation in meningiomas is associated with worse prognosis and is a biomarker of World Health Organization (WHO) grade 3 meningioma in the 2021 WHO CNS Tumor Classification. We investigated whether TERTp-mutant meningiomas represent a clinically and molecularly homogenous group and how they interact with other molecular biomarkers.
Methods: We analyzed clinical and molecular data of 693 meningiomas from twelve institutions with next-generation TERTp sequencing (Figure 1). Chromosomal copy number (CN) was obtained from microarray or derived from DNA methylation.
Results: 55 meningiomas were TERTp-mutant and 638 were TERTp-wildtype (n=27 WHO grade 3). Of TERTp-mutant cases, 50.9% were in male patients (n=28) and 49.1% were in female patients (n=27). The median age was 66 (IQR 60-72) years. TERTp-mutant meningiomas are enriched for aggressive characteristics, with a median of 7.5 mitoses per 10 HPF and a median Ki-67 proliferation index of 15.0%. 67.9% (36/53) of TERTp-mutant meningiomas recurred (median 12.0 months) and 31.9% (15/47) died (median 17.4 months) with an average follow-up time of 3.0 years. Furthermore, TERTp-mutant and TERTp-wildtype WHO grade 3 meningiomas exhibit similar overall survival (OS) and recurrence-free survival (RFS) (Figure 2A,B).
While TERTp-mutant meningiomas are aggressive as a cohort, they represent a clinically and molecularly heterogeneous group. Nearly all TERTp-mutant meningiomas (91.8%) showed concurrent CN aberrations, with frequent loss of chromosome 1p (77.6%) (Figure 3). Data was available for 47 TERTp-mutated meningiomas to calculate an Integrated Grade, a 3-tiered grading scheme that incorporates mitotic count, loss of high-risk chromosomes, and CDKN2A/B status. Interestingly, 6.4% (3/47) of TERTp-mutant meningiomas were Integrated Grade 1, suggesting that they occurred in the absence of additional highly aggressive features, and none of these three meningiomas recurred with an average follow-up of 8.1 years.
We determined WHO grade for 52 TERTp-mutant meningiomas without upgrading tumors to grade 3 solely based on the presence of TERTp mutation (‘adjusted WHO grade’) (10 grade 1, 14 grade 2, 28 grade 3). RFS across adjusted grades of TERTp-mutant meningiomas differed significantly (p<0.005) (Figure 4A). After stratification by adjusted WHO grade, TERTp-mutant and wildtype meningiomas did not differ in RFS (Figure 4B).
CDKN2A/B locus was lost in 44.9% (22/49) of TERTp-mutant meningiomas. 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) (Figure 4C,D).
On multivariate analysis, CDKN2A/B loss (odds ratio [OR] 6.308, p<0.004; OR 5.859, p<0.003) and chromosome 1p loss (OR 2.668, p<0.003; OR 2.956, p<0.006) were associated with an increased risk of both recurrence and death. TERTp-mutation, however, was not significantly associated with either recurrence (OR 2.317, p=0.07) or death (OR 0.401, p=0.118).
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.