DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management
Author:
Nassiri Farshad12, Mamatjan Yasin2, Suppiah Suganth12, Badhiwala Jetan H2, Mansouri Sheila2, Karimi Shirin2, Saarela Olli3, Poisson Laila4, Gepfner-Tuma Irina5, Schittenhelm Jens6, Ng Ho-Keung7, Noushmehr Houtan8, Harter Patrick9, Baumgarten Peter10, Weller Michael11ORCID, Preusser Matthias12, Herold-Mende Christel13, Tatagiba Marcos14, Tabatabai Ghazaleh5, Sahm Felix15, von Deimling Andreas15, 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 Gelareh1216, Aldape Kenneth D1217,
Affiliation:
1. Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada 2. MacFeeters-Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada 3. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada 4. Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, USA 5. Interdisciplinary Division of Neuro-Oncology, Hertie Institute for Clinical Brain Research & Center for CNS Tumors, Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany 6. Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany 7. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China 8. Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA 9. Edinger Institute (Institute of Neurology), Goethe-University, Frankfurt am Main, Germany 10. Department of Neurosurgery, Goethe-University, Frankfurt am Main, Germany 11. Department of Neurology, University Hospital Zurich, Zurich, Switzerland 12. Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center CNS Unit, Medical University of Vienna, Vienna, Austria 13. Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany 14. Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany 15. Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany 16. Division of Neurosurgery, University Health Network, Toronto, Ontario, Canada 17. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
Abstract
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.
Funder
Brain Tumor Charity Quest for Cures Canadian Institute of Health Research‒Institute of Cancer Research Operating Grant
Publisher
Oxford University Press (OUP)
Subject
Cancer Research,Neurology (clinical),Oncology
Cited by
186 articles.
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