DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis.
- Sahm F Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Schrimpf D Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
- Stichel D Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Jones DTW Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Hielscher T Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Schefzyk S Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
- Okonechnikov K Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Koelsche C Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Reuss DE Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Capper D Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Sturm D Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Haematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
- Wirsching HG Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
- Berghoff AS Institute of Neurology, Medical University of Vienna, Vienna, Austria.
- Baumgarten P Neurological Institute (Edinger-Institute), Goethe University, Frankfurt, Germany.
- Kratz A Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Huang K Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Wefers AK Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Hovestadt V Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Sill M Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Ellis HP Brain Tumour Research Group, Institute of Clinical Neurosciences, Southmead Hospital, University of Bristol, Bristol, UK.
- Kurian KM Brain Tumour Research Group, Institute of Clinical Neurosciences, Southmead Hospital, University of Bristol, Bristol, UK.
- Okuducu AF Department of Pathology, University Hospital Nürnberg, Nürnberg, Germany.
- Jungk C Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
- Drueschler K Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany.
- Schick M Genomics and Proteomics Core Facility, Micro-Array Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Bewerunge-Hudler M Genomics and Proteomics Core Facility, Micro-Array Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Mawrin C Department of Neuropathology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
- Seiz-Rosenhagen M Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany.
- Ketter R Department of Neurosurgery, Saarland University, Homburg, Germany.
- Simon M Department of Neurosurgery, Evangelische Krankenhaus Bielefeld, Bielefeld, Germany.
- Westphal M Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
- Lamszus K Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
- Becker A Department of Neuropathology, University of Bonn, Bonn, Germany.
- Koch A Department of Neuropathology, Charité Medical University, Berlin, Germany.
- Schittenhelm J Department of Neuropathology, University Hospital Tübingen, Tübingen, Germany.
- Rushing EJ Department of Neuropathology, University Hospital and University of Zurich, Zurich, Switzerland.
- Collins VP Department of Molecular Histopathology, University of Cambridge, Cambridge, UK.
- Brehmer S Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany.
- Chavez L Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Platten M 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.
- Hänggi D Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany.
- Unterberg A Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
- Paulus W Institute of Neuropathology, University Hospital Münster, Münster, Germany.
- Wick W Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany.
- Pfister SM Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Haematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
- Mittelbronn M Neurological Institute (Edinger-Institute), Goethe University, Frankfurt, Germany.
- Preusser M Department of Medicine I, CNS Tumours Unit, Medical University of Vienna, Vienna, Austria.
- Herold-Mende C Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
- Weller M Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
- von Deimling A 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.
- 2017-03-19
Published in:
- The Lancet. Oncology. - 2017
DNA Copy Number Variations
DNA Methylation
DNA Mutational Analysis
DNA-Binding Proteins
Disease Progression
Disease-Free Survival
Female
Genome
Humans
Kruppel-Like Transcription Factors
Male
Meningeal Neoplasms
Meningioma
Neoplasm Grading
Neoplasm Recurrence, Local
Neurofibromin 2
Nuclear Proteins
Proto-Oncogene Proteins c-akt
Retrospective Studies
Sequence Analysis, RNA
Smoothened Receptor
Survival Rate
Transcription Factors
Transcriptome
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
English
BACKGROUND
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.
METHODS
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.
FINDINGS
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.
INTERPRETATION
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.
FUNDING
German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.
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.
METHODS
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.
FINDINGS
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.
INTERPRETATION
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.
FUNDING
German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1016/S1470-2045(17)30155-9
- PMID 28314689
- Persistent URL
- https://folia.unifr.ch/global/documents/30023
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