DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis.
The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups.



In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip.



We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma.



DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma.



German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Felix
F
Sahm
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
Daniel
D
Schrimpf
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Damian
D
Stichel
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
David T W
DTW
Jones
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Thomas
T
Hielscher
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
Sebastian
S
Schefzyk
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Konstantin
K
Okonechnikov
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Christian
C
Koelsche
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
David E
DE
Reuss
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
David
D
Capper
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Haematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
Dominik
D
Sturm
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
Hans-Georg
HG
Wirsching
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Anna Sophie
AS
Berghoff
Neurological Institute (Edinger-Institute), Goethe University, Frankfurt, Germany.
Peter
P
Baumgarten
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Annekathrin
A
Kratz
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Kristin
K
Huang
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Annika K
AK
Wefers
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Volker
V
Hovestadt
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Martin
M
Sill
Brain Tumour Research Group, Institute of Clinical Neurosciences, Southmead Hospital, University of Bristol, Bristol, UK.
Hayley P
HP
Ellis
Brain Tumour Research Group, Institute of Clinical Neurosciences, Southmead Hospital, University of Bristol, Bristol, UK.
Kathreena M
KM
Kurian
Department of Pathology, University Hospital Nürnberg, Nürnberg, Germany.
Ali Fuat
AF
Okuducu
Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
Christine
C
Jungk
Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany.
Katharina
K
Drueschler
Genomics and Proteomics Core Facility, Micro-Array Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Matthias
M
Schick
Genomics and Proteomics Core Facility, Micro-Array Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Melanie
M
Bewerunge-Hudler
Department of Neuropathology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
Christian
C
Mawrin
Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany.
Marcel
M
Seiz-Rosenhagen
Department of Neurosurgery, Saarland University, Homburg, Germany.
Ralf
R
Ketter
Department of Neurosurgery, Evangelische Krankenhaus Bielefeld, Bielefeld, Germany.
Matthias
M
Simon
Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Manfred
M
Westphal
Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Katrin
K
Lamszus
Department of Neuropathology, University of Bonn, Bonn, Germany.
Albert
A
Becker
Department of Neuropathology, Charité Medical University, Berlin, Germany.
Arend
A
Koch
Department of Neuropathology, University Hospital Tübingen, Tübingen, Germany.
Jens
J
Schittenhelm
Department of Neuropathology, University Hospital and University of Zurich, Zurich, Switzerland.
Elisabeth J
EJ
Rushing
Department of Molecular Histopathology, University of Cambridge, Cambridge, UK.
V Peter
VP
Collins
Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany.
Stefanie
S
Brehmer
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Lukas
L
Chavez
Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany; Neurology Clinic, University Hospital Mannheim, Mannheim, Germany.
Michael
M
Platten
Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany.
Daniel
D
Hänggi
Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
Andreas
A
Unterberg
Institute of Neuropathology, University Hospital Münster, Münster, Germany.
Werner
W
Paulus
Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany.
Wolfgang
W
Wick
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Haematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
Stefan M
SM
Pfister
Neurological Institute (Edinger-Institute), Goethe University, Frankfurt, Germany.
Michel
M
Mittelbronn
Department of Medicine I, CNS Tumours Unit, Medical University of Vienna, Vienna, Austria.
Matthias
M
Preusser
Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
Christel
C
Herold-Mende
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
Michael
M
Weller
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: andreas.vondeimling@med.uni-heidelberg.de.
Andreas
A
von Deimling
D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D016678:Genome; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D008577:Meningeal Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D008579:Meningioma / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D025581:Neurofibromin 2 / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012189:Retrospective Studies; D017423:Sequence Analysis, RNA; D000072086:Smoothened Receptor / Q000235:genetics; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics
C112476:ARID1A protein, human; C497837:ARID1B protein, human; D004268:DNA-Binding Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D025581:Neurofibromin 2; D009687:Nuclear Proteins; C491023:SMO protein, human; D000072086:Smoothened Receptor; C486460:TRAF7 protein, human; D014157:Transcription Factors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt