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 ot...
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
September 2025
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| In: |
The lancet. Oncology
Year: 2025, Jahrgang: 26, Heft: 9, Pages: 1178-1190 |
| ISSN: | 1474-5488 |
| DOI: | 10.1016/S1470-2045(25)00422-X |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/S1470-2045(25)00422-X Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S147020452500422X 
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| Verfasserangaben: | Karenna J Groff, Ruchit V Patel, Yang Feng, Hia S Ghosh, Miguel A Millares Chavez, Joseph O'Brien, William C Chen, Vijay Nitturi, Akshay V Save, Mark W Youngblood, Craig M Horbinski, James P Chandler, Felix Ehret, Chloe Gui, Justin Z Wang, Kristen Park, Sonia Ajmera, Marc Rosenblum, Abigail K Suwala, Catena Kresbach, Christopher W Mount, Ulrich Schüller, Sandro Santagata, Felix Sahm, Tejus A Bale, Christina Jackson, Timothy E Richardson, Chunyu Cai, Farshad Nassiri, Gelareh Zadeh, David Kaul, David Capper, Stephen T Magill, John G Golfinos, Chandra Sen, Akash J Patel, David R Raleigh, Jennifer Moliterno, Donato Pacione, Matija Snuderl, Wenya Linda Bi |
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| 245 | 1 | 4 | |a The effect of TERT promoter mutation on predicting meningioma outcomes |b a multi-institutional cohort analysis |c Karenna J Groff, Ruchit V Patel, Yang Feng, Hia S Ghosh, Miguel A Millares Chavez, Joseph O'Brien, William C Chen, Vijay Nitturi, Akshay V Save, Mark W Youngblood, Craig M Horbinski, James P Chandler, Felix Ehret, Chloe Gui, Justin Z Wang, Kristen Park, Sonia Ajmera, Marc Rosenblum, Abigail K Suwala, Catena Kresbach, Christopher W Mount, Ulrich Schüller, Sandro Santagata, Felix Sahm, Tejus A Bale, Christina Jackson, Timothy E Richardson, Chunyu Cai, Farshad Nassiri, Gelareh Zadeh, David Kaul, David Capper, Stephen T Magill, John G Golfinos, Chandra Sen, Akash J Patel, David R Raleigh, Jennifer Moliterno, Donato Pacione, Matija Snuderl, Wenya Linda Bi |
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| 520 | |a 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. | ||
| 700 | 1 | |a Patel, Ruchit V |e VerfasserIn |4 aut | |
| 700 | 1 | |a Feng, Yang |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ghosh, Hia S |e VerfasserIn |4 aut | |
| 700 | 1 | |a Millares Chavez, Miguel A |e VerfasserIn |4 aut | |
| 700 | 1 | |a O'Brien, Joseph |e VerfasserIn |4 aut | |
| 700 | 1 | |a Chen, William C |e VerfasserIn |4 aut | |
| 700 | 1 | |a Nitturi, Vijay |e VerfasserIn |4 aut | |
| 700 | 1 | |a Save, Akshay V |e VerfasserIn |4 aut | |
| 700 | 1 | |a Youngblood, Mark W |e VerfasserIn |4 aut | |
| 700 | 1 | |a Horbinski, Craig M |e VerfasserIn |4 aut | |
| 700 | 1 | |a Chandler, James P |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ehret, Felix |e VerfasserIn |4 aut | |
| 700 | 1 | |a Gui, Chloe |e VerfasserIn |4 aut | |
| 700 | 1 | |a Wang, Justin Z |e VerfasserIn |4 aut | |
| 700 | 1 | |a Park, Kristen |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ajmera, Sonia |e VerfasserIn |4 aut | |
| 700 | 1 | |a Rosenblum, Marc |e VerfasserIn |4 aut | |
| 700 | 1 | |a Suwala, Abigail Kora |e VerfasserIn |0 (DE-588)1190741725 |0 (DE-627)1669311619 |4 aut | |
| 700 | 1 | |a Kresbach, Catena |e VerfasserIn |4 aut | |
| 700 | 1 | |a Mount, Christopher W |e VerfasserIn |4 aut | |
| 700 | 1 | |a Schüller, Ulrich |e VerfasserIn |4 aut | |
| 700 | 1 | |a Santagata, Sandro |e VerfasserIn |4 aut | |
| 700 | 1 | |a Sahm, Felix |d 1984- |e VerfasserIn |0 (DE-588)1022852132 |0 (DE-627)717318478 |0 (DE-576)366075020 |4 aut | |
| 700 | 1 | |a Bale, Tejus A |e VerfasserIn |4 aut | |
| 700 | 1 | |a Jackson, Christina |e VerfasserIn |4 aut | |
| 700 | 1 | |a Richardson, Timothy E |e VerfasserIn |4 aut | |
| 700 | 1 | |a Cai, Chunyu |e VerfasserIn |4 aut | |
| 700 | 1 | |a Nassiri, Farshad |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Kaul, David |e VerfasserIn |4 aut | |
| 700 | 1 | |a Capper, David |e VerfasserIn |4 aut | |
| 700 | 1 | |a Magill, Stephen T |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Sen, Chandra |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Pacione, Donato |e VerfasserIn |4 aut | |
| 700 | 1 | |a Snuderl, Matija |e VerfasserIn |4 aut | |
| 700 | 1 | |a Bi, Wenya Linda |e VerfasserIn |4 aut | |
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