DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management
Authors: Nassiri Farshad , Mamatjan Yasin , Suppiah Suganth , Badhiwala Jetan H , Mansouri Sheila , Karimi Shirin , Saarela Olli , Poisson Laila , Gepfner-Tuma Irina , Schittenhelm Jens , Ng Ho-Keung , Noushmehr Houtan , Harter Patrick , Baumgarten Peter , Weller Michael , Preusser Matthias , Herold-Mende Christel , Tatagiba Marcos , Tabatabai Ghazaleh , Sahm Felix , von Deimling Andreas ,   International Consortium on Meningiomas, Aldape Kenneth , Au Karolyn , Barnhartz-Sloan Jill , Bi Wenya Linda , Brastianos Priscilla K , Butowski Nicholas , Carlotti Carlos , Cusimano Michael D , DiMeco Francesco , Drummond Katharine , Dunn Ian F , Galanis Evanthia , Giannini Caterina , Goldbrunner Roland , Griffith Brent , Hashizume Rintaro , Hanemann C Oliver , Herold-Mende Christel , Horbinski Craig , Huang Raymond Y , James David , Jenkinson Michael D , Jungk Christine , Kaufman Timothy J , Krischek Boris , Lachance Daniel , Lafougère Christian , Lee Ian , Liu Jeff C , Mamatjan Yasin , Malta Tathiane M , Mawrin Christian , McDermott Michael , Munoz David , Nassiri Farshad , Noushmehr Houtan , Ng Ho-Keung , Perry Arie , Pirouzmand Farhad , Poisson Laila M , Pollo Bianca , Raleigh David , Sahm Felix , Saladino Andrea , Santarius Thomas , Schichor Christian , Schultz David , Schmidt Nils O , Selman Warren , Sloan Andrew , Spears Julian , Snyder James , Suppiah Suganth , Tabatabai Ghazaleh , Tatagiba Marcos , Tirapelli Daniela , Tonn Joerg C , Tsang Derek , Vogelbaum Michael A , von Deimling Andreas , Wen Patrick Y , Walbert Tobias , Westphal Manfred , Workewych Adriana M , Zadeh Gelareh , Zadeh Gelareh , Aldape Kenneth D 
Published: April 2019

Abstract

Background
Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma.

Methods
DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts.

Results
The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P < 0.001) with clinical implications.

Conclusions
The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.