The effect of TERT promoter mutation on predicting meningioma outcomes: a multi-institutional cohort analysis

Background

Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis. We sought to characterise the role of TERTp mutation in meningioma and guide TERTp sequencing.

Methods

We identified 1492 patients of all ages who had previously received surgery for meningioma across 14 medical centres in the USA, Canada, and Germany. Patients were eligible if they had post-surgical clinical or radiographical assessment of the resection site, and TERTp status evaluated by Nov 1, 2024. Multi-modal profiling was used to assess TERTp mutation, focal gene alterations—including CDKN2A/B loss—and copy number alterations. An adjusted WHO grade was calculated for TERTp-mutant meningiomas, incorporating all WHO criteria except TERTp status. Kaplan–Meier curves and multivariable Cox proportional hazards models were used to quantify the effect of TERTp mutation on the endpoints of overall survival and recurrence-free survival across adjusted WHO grade and co-occurring molecular alterations.

Findings

64 (4·3%) of 1492 meningiomas were TERTp-mutant and 1428 (95·7%) were TERTp-wildtype. Of the TERTp-mutant meningiomas, 33 (51·6%) were from female patients and 31 (48·4%) were from male patients, and the overall median age was 67 years (IQR 60–75). Of the wildtype meningiomas, 965 (67·6%) were from female patients and 463 (32·4%) were from male patients, and the overall median age of the patients was 59 years (IQR 48–70). Data on race was inconsistently reported and thus excluded. The TERTp-mutant patients had a 5-year overall survival (49·4% [95% CI 33·7–72·4]) and 5-year recurrence-free survival (27·6% [95% CI 16·8–45·5]) resembling that of patients with WHO grade 3 TERTp-wildtype tumours (5-year overall survival 32·3% [95% CI 17·2–60·5], p=0·28, 5-year recurrence-free survival 14·3% [5·8–35·2], p=0·28). However, the TERTp-mutant group had heterogenous histological grading and was enriched for aggressive molecular features, with 1p loss present in 44 (77·2%) of 57 profiled tumours and CDKN2A/B loss in 24 (41·4%) of the 58 profiled tumours. Adjusting tumour grade revealed a subset of TERTp-mutant meningiomas that were more molecularly and clinically benign. Among TERTp-mutant tumours, CDKN2A/B loss played a defining role in stratifying tumour behaviour. Multivariable analysis confirmed this, with CDKN2A/B loss being significantly associated with shorter overall survival (HR 3·04 [95% CI 1·67–5·52], p=0·00026) and faster time to recurrence (HR 5·22 [95% CI 3·10–8·79], p<0·0001), while TERTp-mutation did not independently affect overall survival (HR 1·00 [95% CI 0·53–1·87], p=0·99) or recurrence-free survival (1·17 [95% CI 0·75–1·83], p=0·49). Sequencing for TERTp-mutation demonstrated clinical impact only among histologically WHO grade 2 meningiomas.

Interpretation

The indolent behaviour of certain TERTp-mutant meningiomas suggests that TERTp mutation is not sufficient to assign the most aggressive meningioma grade. Instead, TERT sequencing might offer prognostic utility in identifying high-risk cases among WHO grade 2 meningiomas.

Funding

National Institutes of Health, National Institute of Neurological Disorders and Stroke, Friedberg Charitable Foundation, Courtney Meningioma Research Fund, Fleming Meningioma Research Fund, and the Gray Family Foundation.