Sybren L N Maas1,2, Damian Stichel1, Thomas Hielscher3, Philipp Sievers1, Anna S Berghoff4,5, Daniel Schrimpf1, Martin Sill6, Philipp Euskirchen7, Christina Blume1, Areeba Patel1, Helin Dogan1, David Reuss1, Hildegard Dohmen8, Marco Stein8,9, Annekathrin Reinhardt1, Abigail K Suwala1, Annika K Wefers1, Peter Baumgarten10, Franz Ricklefs11, Elisabeth J Rushing12, Melanie Bewerunge-Hudler13, Ralf Ketter14, Jens Schittenhelm15, Zane Jaunmuktane16,17, Severina Leu18, Fay E A Greenway19, Leslie R Bridges20, Timothy Jones19, Conor Grady21, Jonathan Serrano21, John Golfinos21, Chandra Sen21, Christian Mawrin22, Christine Jungk23, Daniel Hänggi24, Manfred Westphal11, Katrin Lamszus11, Nima Etminan25, Gerhard Jungwirth23, Christel Herold-Mende26, Andreas Unterberg23, Patrick N Harter27,28, Hans-Georg Wirsching29, Marian C Neidert30, Miriam Ratliff25, Michael Platten31, Matija Snuderl32, Kenneth D Aldape33, Sebastian Brandner16,34, Jürgen Hench18, Stephan Frank18, Stefan M Pfister6,35,36, David T W Jones6,37, Guido Reifenberger38,39, Till Acker8, Wolfgang Wick40,41, Michael Weller29, Matthias Preusser5, Andreas von Deimling1, Felix Sahm1,6. 1. Department of Neuropathology, University Hospital Heidelberg and CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 2. Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 3. Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany. 4. Institute of Neurology, Medical University of Vienna, Vienna, Austria. 5. Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria. 6. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. 7. Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany. 8. Department of Neuropathology, University Hospital Gießen, Giessen, Germany. 9. Department of Neurosurgery, University Hospital Gießen, Giessen, Germany. 10. Department of Neurosurgery, University Hospital Frankfurt, Frankfurt, Germany. 11. Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany. 12. Department of Neuropathology, University Hospital Zurich, Zürich, Switzerland. 13. Genome and Proteome Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany. 14. Department of Neurosurgery, University Hospital Homburg, Homburg, Germany. 15. Department of Neuropathology, University Hospital Tübingen, Tübingen, Germany. 16. Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, United Kingdom. 17. Department of Clinical and Movement Neurosciences and Queen Square Brain Bank for Neurological Disorders, Queen Square Institute of Neurology, University College London, London, United Kingdom. 18. Department of Neuropathology, University Hospital Basel, Basel, Switzerland. 19. Department of Neurosurgery, St George's Hospital, London, United Kingdom. 20. Department of Cellular Pathology, St George's Hospital, London, United Kingdom. 21. Department of Neurosurgery, NYU Langone Hospital, New York, NY. 22. Department of Neuropathology, University Hospital Magdeburg, Magdeburg, Germany. 23. Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany. 24. Department of Neurosurgery, University Hospital Düsseldorf, Düsseldorf, Germany. 25. Department of Neurosurgery, University Medicine Mannheim, Mannheim, Germany. 26. Division of Exp. Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany. 27. Neurological Institute (Edinger Institute), University Hospital Frankfurt, Frankfurt, Germany. 28. Frankfurt Cancer Institute (FCI) and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Heidelberg, Germany. 29. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland. 30. Department of Neurosurgery, Kantonsspital St Gallen, St Gallen, Switzerland. 31. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Heidelberg, Germany. 32. Department of Pathology, NYU Grossman School of Medicine, New York, NY. 33. Laboratory of Pathology, National Cancer Insitute, Bethesda, MD. 34. Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom. 35. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 36. Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany. 37. Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. 38. Institute of Neuropathology, Heinrich Heine University Medical Faculty, Düsseldorf, Germany. 39. German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Germany. 40. Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 41. Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Abstract
PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.
PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.
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