Gui Chloe, Wang Justin Z, Patil Vikas, Landry Alexander P, Singh Olivia, Castelo-Branco Pedro, Tabori Uri, Aldape Kenneth, Behling Felix, Barnholtz-Sloan Jill S, Horbinski Craig, Tabatabai Ghazaleh, Ajisebutu Andrew, Liu Jeff, Patel Zeel, Yakubov Rebeca, Kaloti Ramneet, Ellenbogen Yosef, Wilson Christopher, Cohen-Gadol Aaron, Tatagiba Marcos, Holland Eric C, Sloan Andrew E, Chotai Silky, Chambless Lola B, Gao Andrew, Makarenko Serge, Yip Stephen, Nassiri Farshad, Zadeh Gelareh
MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Lancet Oncol. 2025 Sep;26(9):1191-1203. doi: 10.1016/S1470-2045(25)00267-0.
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.
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.
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).
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.
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.
端粒酶逆转录酶（TERT）启动子突变是脑膜瘤中一种罕见的生物标志物，与TERT异常表达及无进展生存期缩短相关。尽管TERT高表达是TERT启动子突变肿瘤的特征，但在TERT启动子野生型的肿瘤中也有观察到。本研究旨在调查脑膜瘤中TERT表达的患病率及其与预后的关联。
这项多机构队列研究回顾性收集了2000年1月1日至2024年12月31日期间在加拿大多伦多西部医院手术切除的1241例脑膜瘤的临床和分子数据（n = 380；发现队列）以及加拿大、德国和美国的外部机构的数据（n = 861；验证队列）。所有患者年龄均在18岁及以上。通过桑格测序和批量RNA测序确定TERT启动子突变和TERT表达。主要结局为有无TERT启动子突变的脑膜瘤中TERT的表达情况，以及TERT表达肿瘤与未表达TERT肿瘤的无进展生存期差异。使用Cox回归和Kaplan-Meier分析评估生存情况。
在2000年1月1日至2024年12月31日期间，收集了临床人口统计学和肿瘤特征数据。发现队列的中位随访时间为6.2年（四分位间距1.7 - 12.5年），验证队列的中位随访时间为3.3年（1.3 - 3.8年）。在整个队列中有性别数据的1181例患者中，777例（65.8%）为女性；404例（34.2%）为男性。在547例TERT启动子野生型的脑膜瘤中，157例（28.7%）有TERT表达；根据RNA数据，在604例总体脑膜瘤中，193例（32.0%）有TERT表达。总体而言，TERT表达赋予了中等的无进展生存期，短于TERT阴性肿瘤患者，但长于TERT启动子突变患者。在发现队列中，TERT启动子野生型且表达TERT的肿瘤患者的中位无进展生存期为3.2年（95%置信区间1.7 - 6.5年），TERT阴性的TERT启动子野生型肿瘤患者为16.0年（7.1年至未达到；p = 0.0021），TERT启动子突变患者为1.6年（0.9年至未达到；p = 0.039）。这些结果在验证队列中得到了重复。在每个世界卫生组织（WHO）分级内，TERT表达赋予的无进展生存期与高一级的TERT阴性脑膜瘤相当。TERT表达的1级肿瘤的无进展生存期与TERT阴性的2级肿瘤相似（中位未达到[95%置信区间16.0年至未达到]对8.2年[95%置信区间4.5年至未达到]；p = 0.59）。TERT表达的2级肿瘤的无进展生存期与TERT阴性的3级肿瘤相似（中位3.6年[2.4至5.3年]对3.8年[2.3年至未达到]；p = 0.42）。多变量回归显示，即使在调整了TERT启动子突变、CDKN2A/B缺失、染色体1p/22q状态和WHO分级后，TERT表达仍与较短的无进展生存期相关（风险比1.85[95%置信区间1.33 - 2.57]；p = 0.0002）。
脑膜瘤中的TERT表达可预测疾病早期进展，独立于TERT启动子突变和其他标志物，可能有必要将表达TERT的脑膜瘤重新分类为更高的WHO分级。
加拿大卫生研究院、英国脑肿瘤慈善机构、大学健康网络基金会、玛丽·亨特脑膜瘤研究基金、V基金会和美国国立卫生研究院。
