Landry, Alexander P.Wang, Justin Z.Patil, VikasGui, ChloeMamatjan, YasinPatel, ZeelYakubov, RebeccaKaloti, RamneetHabibi, ParnianWilson, MarkAjisebutu, AndrewEllenbogen, YosefWei, QingxiaSingh, OliviaSosa, JulioMansouri, SheilaWilson, ChristopherCohen-Gadol, Aaron A.Virtanen, PiiamariaBurket, NoahBlackwell, MatthewKoenig, JennaAlfonso, AnthonyDavis, JosephZaazoue, Mohamed A.Tabatabai, GhazalehTatagiba, MarcosBehling, FelixBarnholtz-Sloan, Jill S.Sloan, Andrew E.Chotai, SilkyChambless, Lola B.Mansouri, AlirezaEhret, FelixCapper, DavidTsang, Derek S.Aldape, KennethGao, AndrewInternational Consortium on Meningiomas (ICOM)Nassiri, FarshadZadeh, Gelareh2025-06-182025-06-182025Landry AP, Wang JZ, Patil V, et al. Validation and next-generation update of a DNA methylation-based recurrence predictor for meningioma: A multicenter prospective study. Neuro Oncol. 2025;27(4):1004-1016. doi:10.1093/neuonc/noae236https://hdl.handle.net/1805/48849Background: We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion since its original publication. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation predictor compatible with newer methylation arrays. Methods: Genome-wide methylation profiles were generated with the Illumina EPICArray. The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. An nomogram was generated by incorporating our methylation predictor with WHO grade and the extent of resection. Results: A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and an external cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperform the 2021 WHO grade in predicting early postoperative recurrence. Dichotomizing patients into grade-specific risk subgroups was predictive of outcomes within both WHO grades 1 and 2 tumors (P < .05), whereas all WHO grade 3 tumors were considered high-risk. Multivariable Cox regression demonstrated the benefit of adjuvant radiotherapy (RT) in high-risk cases specifically, reinforcing its informative role in clinical decision-making. Finally, our next-generation predictor contains nearly 10-fold fewer features than the original model, allowing for targeted arrays. Conclusions: This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms the 2021 WHO grading in predicting time to recurrence. We make this available as a point-and-click tool that will improve prognostication, inform patient selection for RT, and allow for molecularly stratified clinical trials.en-USAttribution-NonCommercial 4.0 InternationalDNA methylationMeningiomaNeuro-oncologyOutcome predictionPrognosisArticle