Authors: Farshad Nassiri, MD; Yasin Mamatjan; Suganth Suppiah; Jetan Badhiwala; Olli Saarela; Laila Poisson; Houtan Noushmehr; Felix Sahm; Andreas von Deimling; Kenneth Aldape; Gelareh Zadeh (Toronto, Ontario, Canada)

Introduction: Difficulties in predicting recurrence risk for individual patients with meningioma using current classification systems limits appropriate selection of patients who may benefit from adjuvant therapy to delay recurrence. Recent data suggests the utility of DNA methylation as a clinically-relevant biomarker. We aimed to develop and validate a combined molecular and clinical predictor of recurrence for individual patients with meningiomas. Methods: In this multi-centre study, DNA methylation profiles from 486 meningioma tumors were used to develop and validate a predictor of 5-year recurrence-free-survival (RFS). Cox modelling was used to select features for model generation in a training cohort (N=228 patients) which was then applied to three independent validation cohorts (N=54; N=140; N=64 patients). Penalized-Cox modeling was used to generate a 5-year meningioma recurrence score based on a nomogram that integrated the methylome-based predictor with prognostic clinical factors. Results: The methylome-based predictor of 5-year RFS performed favourably compared to a grade-based predictor when tested using the three validation cohorts (ΔAUC =0 . 10, 95%CI 0 . 03 – 0 . 018) and was independently associated with RFS after adjusting for tumour grade, extent of resection and burden of copy number alterations (EOR; HR 3 . 6, 95%CI 1 . 8 – 7 . 2, P < 0.001). A nomogram combining the methylome-predictor with clinical factors demonstrated greater accuracy than a nomogram using clinical factors alone in two independent validation cohorts (ΔAUC = 0.20 andΔAUC = 0.22%) with an overall accuracy of approximately 87% and resulted in two different risk groups with distinct recurrence patterns (HR 7.7, 95%CI 5.3 – 11.1, P < 0.001) and clinical implications. Conclusion: The tools developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors that could be used to individualize decisions regarding the need for adjuvant radiation therapy versus observation alone in patients with meningiomas.