TERTP Mutant Meningiomas in the Absence of Concurrent Aggressive Features Exhibit Better Outcomes than TERTP Wild-Type Who Grade 3 Meningiomas

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 ([Fig. 1]). Chromosomal copy number (CN) was obtained from microarray or derived from DNA methylation.

Results: A total of 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) ([Fig. 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%; [Fig. 3]). Data was available for 47 TERTp-mutated meningiomas to calculate an integrated grade, a three-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, and 28 grade 3). RFS across adjusted grades of TERTp-mutant meningiomas differed significantly (p < 0.005; [Fig. 4A]). After stratification by adjusted WHO grade, TERTp-mutant and wild-type meningiomas did not differ in RFS ([Fig. 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; [Fig. 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).

Conclusion: 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.

Publication History

Article published online:
07 February 2025