Analysis of TERT association with clinical outcome in meningiomas: a multi-institutional cohort study - 02/09/25

Doi : 10.1016/S1470-2045(25)00267-0

Chloe Gui, MD ^a,^b,^c, Justin Z Wang, MD PhD ^a,^b,^c, Vikas Patil, PhD ^a,^c, Alexander P Landry, MD ^a,^b,^c, Olivia Singh, MSc ^a,^c, Pedro Castelo-Branco, PhD ^d,^e,^f, Uri Tabori, ProfMD ^g, Kenneth Aldape, MD ^h, Felix Behling, MD ⁱ, Jill S Barnholtz-Sloan, PhD ^j,^k, Craig Horbinski, ProfMD PhD ^l,^m, Ghazaleh Tabatabai, ProfMD PhD ^n,^o, Andrew Ajisebutu, MD ^a,^b,^c, Jeff Liu, PhD ^a,^c, Zeel Patel, BSc ^p, Rebeca Yakubov, MSc ^a,^c, Ramneet Kaloti, BSc ^a,^c, Yosef Ellenbogen, MD ^a,^b,^c, Christopher Wilson, MD ^q, Aaron Cohen-Gadol, ProfMD ^r, Marcos Tatagiba, ProfMD PhD ⁱ, Eric C Holland, MD PhD ^s, Andrew E Sloan, ProfMD ^t,^u, Silky Chotai, MD ^v,^w, Lola B Chambless, ProfMD ^v, Andrew Gao, MD MSc ^x, Serge Makarenko, MD ^y, Stephen Yip, MD PhD ^z, Farshad Nassiri, MD PhD ^a,^b,^c,^{*
Jointly supervised the work}, Gelareh Zadeh, ProfMD PhD ^a,^b,^c,^aa,^{*
Jointly supervised the work}⁎
and
The International Consortium on Meningiomas (ICOM)^†
Members are listed in the Supplementary Material

^a MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada

^b Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada

^c Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

^d Faculty of Medicine and Biomedical Sciences, University of Algarve, Gambelas Campus, Faro, Portugal

^e Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Faro, Portugal

^f Champalimaud Research Program, Champalimaud Centre for the Unknown, Lisbon, Portugal

^g Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada

^h Laboratory of Pathology, National Cancer Institute Centre for Cancer Research, Bethesda, MD, USA

ⁱ Department of Neurosurgery, Center for Neuro-Oncology, Comprehensive Cancer Center, Eberhard Karls University Tübingen, Tübingen, Germany

^j Trans Divisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

^k Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, MD, USA

^l Department of Pathology, Northwestern University, Chicago, IL, USA

^m Lou & Jean Malnati Brain Tumor Institute at the Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA

ⁿ German Cancer Consortium, DKFZ Partner Site Tübingen, Tübingen, Germany

^o Department of Neurology and Interdisciplinary Neuro-Oncology, Center for Neuro-Oncology, Comprehensive Cancer Center, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany

^p Temerty School of Medicine, University of Toronto, Toronto, ON, Canada

^q Oklahoma State University College of Osteopathic Medicine, Tulsa, OK, USA

^r Department of Neurological Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

^s Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

^t Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

^u Piedmont Brain Tumor Center, Piedmont Health, Atlanta, GA, USA

^v Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, USA

^w Cleveland Clinic Foundation, Cleveland, OH, USA

^x Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

^y Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada

^z Department of Pathology & Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada

^aa Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA

^* Correspondence to: Prof Gelareh Zadeh, Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON M5T 2S8, Canada Division of Neurosurgery Department of Surgery University of Toronto Toronto ON M5T 2S8 Canada

Summary

Background

TERT promoter mutation is a rare biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival. Although high TERT expression is characteristic of tumours with TERT promoter mutations, it has also been observed in tumours with wildtype TERT promoters. This study aimed to investigate the prevalence and prognostic association of TERT expression in meningiomas.

Methods

This multi-institutional cohort study retrospectively collected clinical and molecular data from 1241 meningiomas surgically resected between Jan 1, 2000, and Dec 31, 2024, at Toronto Western Hospital, Canada (n=380; discovery cohort) and external institutions in Canada, Germany, and the USA (n=861; validation cohort). All patients were aged 18 years and older. TERT promoter mutation and TERT expression were determined by Sanger and bulk RNA sequencing. The primary outcomes were TERT expression (presence or absence) in meningiomas with and without TERT promoter mutations, and the difference in progression-free survival between tumours expressing TERT and those not expressing TERT. Survival analysis was assessed using Cox regression and Kaplan–Meier analysis.

Findings

Between Jan 1, 2000, and Dec 31, 2024, clinical demographics and tumour characteristics were collected. Median follow-up was 6·2 years (IQR 1·7–12·5) in the discovery cohort and 3·3 years (1·3–3·8) in the validation cohort. 777 (65·8%) of 1181 patients with sex data in the overall cohort were female; 404 (34·2%) were male. TERT was expressed in 157 (28·7%) of 547 wildtype TERT promoter meningiomas and in 193 (32·0%) of 604 overall with RNA data. TERT expression overall conferred an intermediate progression-free survival, shorter than that in patients with TERT-negative tumours but longer than in those with TERT promoter mutations. In the discovery cohort, median progression-free survival was 3·2 years (95% CI 1·7–6·5) in patients with wildtype TERT promoter tumours expressing TERT, 16·0 years (7·1 to not reached; p=0·0021) in patients with TERT-negative wildtype TERT promoter tumours, and 1·6 years (0·9 to not reached; p=0·039) in patients with TERT promoter mutations. These findings were replicated in the validation cohort. Within each WHO grade, TERT expression conferred a progression-free survival equivalent to TERT-negative meningiomas of one grade higher. Grade 1 tumours with TERT expression had a progression-free survival similar to TERT-negative grade 2 tumours (median not reached [95% CI 16·0 to not reached] vs 8·2 years [95% CI 4·5 to not reached]; p=0·59). Grade 2 tumours with TERT expression had a similar progression-free survival to TERT-negative grade 3 tumours (median 3·6 years [2·4 to 5·3] vs 3·8 years [2·3 to not reached]; p=0·42). Multivariable regression showed that TERT expression remained associated with shorter progression-free survival even after adjusting for TERT promoter mutations, CDKN2A/B loss, chromosome 1p/22q status, and WHO grade (hazard ratio 1·85 [95% CI 1·33–2·57]; p=0·0002).

Interpretation

TERT expression in meningiomas predicted earlier disease progression, independent of TERT promoter mutation and other markers, and might warrant reclassification of meningiomas that express TERT to a higher WHO grade.

Funding

Canadian Institutes of Health Research, Brain Tumour Charity UK, University Health Network Foundation, Mary Hunter Meningioma Research Fund, V Foundation, and National Institutes of Health.

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Vol 26 - N° 9

P. 1191-1203 - septembre 2025 Retour au numéro

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Analysis of TERT association with clinical outcome in meningiomas: a multi-institutional cohort study - 02/09/25

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