EPCO-52. MACHINE LEARNING AND MULTI-OMIC ANALYSIS IDENTIFY A MICROENVIRONMENT-DRIVEN MENINGIOMA RISK CONTINUUM UNDERLYING MOLECULAR CLASSIFICATIONS
Neuro-Oncology, vol. 27, pp. v14
Abstract
Abstract Machine learning-based molecular classifications, particularly those using DNA methylation data, have greatly advanced diagnostics for meningioma, the most common type of primary intracranial tumor. Meningiomas have historically been classified into NF2-mutant and NF2-wild-type groups, while additional mutations and copy-number variations associated with progression risk have been incorporated into WHO grading. Several genome-wide methylation-based classification systems have been proposed. The systems, such as the random forest Brain Tumour Classifier, have been incorporated into diagnostic guidelines. However, while a number of core archetypes are shared among the different classifications, discrepancies on the definition and granularity of subtypes remain an obstacle to their clinical application. Understanding the underlying heterogeneity driving these classifications is therefore crucial. Through an integrated analysis of single-nuclei and spatially resolved transcriptomic data, as well as DNA methylation array data from multiple meningioma cohorts, we identified cell types and epigenetic signatures that are associated with increased aggressiveness in meningiomas. The results demonstrated that incremental changes in the tumor microenvironment (TME), particularly shifts in compositions and epigenetic-transcriptomic signatures in tumor-associated monocytes/macrophages and microglia-like cells, have a decisive impact on epigenetic classifications alongside tumor cells, and significantly affect clinical outcome. Therefore, we refine the previously proposed distinct molecular subtypes with a TME-determined risk continuum model for NF2-mutant meningiomas. Based on these discoveries, we additionally designed an immunohistochemistry-based diagnostic approach, which also captures intra-tumoral heterogeneities.
Authors 45
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Leiden University Medical Center · Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam , Rotterdam, Netherlands
Department of Pathology, Leiden University Medical Center , Leiden, Netherlands
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK) , Heidelberg,
Department of Neuropathology, University Hospital Heidelberg , Heidelberg,
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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University of Toronto · Hopp Children's Cancer Center Heidelberg
Affiliation as printed
Department of Radiation Oncology, University of Toronto , Toronto,
Hopp Children’s Cancer Center Heidelberg (KiTZ) , Heidelberg,
Department of Radiation Oncology, University of Toronto, Toronto, Canada
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK) , Heidelberg,
Department of Neuropathology, University Hospital Heidelberg , Heidelberg,
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Affiliation as printed
Department of Biostatistics, German Cancer Research Center (DKFZ) , Heidelberg,
Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK) , Heidelberg,
Department of Neuropathology, University Hospital Heidelberg , Heidelberg,
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Boston Children's Hospital · Dana-Farber Cancer Institute
Affiliation as printed
Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston,
Division of Hematology/Oncology, Boston Children’s Hospital , Boston,
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, USA
Division of Hematology/Oncology, Boston Children's Hospital, Boston, USA
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Affiliation as printed
Division of AI in Oncology, German Cancer Research Centre (DKFZ) , Heidelberg,
Systems Immunology & Single-Cell Biology, German Cancer Research Center (DKFZ) , Heidelberg,
Division of AI in Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
Systems Immunology & Single-Cell Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Hopp Children's Cancer Center Heidelberg
Affiliation as printed
Hopp Children’s Cancer Center Heidelberg (KiTZ) , Heidelberg,
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
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Friedrich-Alexander-Universität Erlangen-Nürnberg
Affiliation as printed
Translational Neurosurgery, Neurosurgical Clinic, Friedrich-Alexander Universität Erlangen-Nürnberg , Erlangen,
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Friedrich-Alexander-Universität Erlangen-Nürnberg
Affiliation as printed
Translational Neurosurgery, Neurosurgical Clinic, Friedrich-Alexander Universität Erlangen-Nürnberg , Erlangen,
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Sorbonne Université · Pitié-Salpêtrière Hospital
Affiliation as printed
Sorbonne Université and Department of Neurosurgery, Pitié Salpêtrière Hospital , Paris,
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Affiliation as printed
Institute of Neuropathology, Faculty of Medicine, University of Freiburg , Freiburg,
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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German Cancer Research Center · Hopp Children's Cancer Center Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) , Heidelberg,
Hopp Children’s Cancer Center Heidelberg (KiTZ) , Heidelberg,
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK) , Heidelberg,
Department of Neuropathology, University Hospital Heidelberg , Heidelberg,
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK) , Heidelberg,
Department of Neuropathology, University Hospital Heidelberg , Heidelberg,
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK) , Heidelberg,
Department of Neuropathology, University Hospital Heidelberg , Heidelberg,
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Affiliation as printed
Faculty of Health, Peninsula Medical School, University of Plymouth, Plymouth, United Kingdom
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Affiliation as printed
Department of Neurosurgery, University Hospital Hamburg , Hamburg,
Department of Neurosurgery, University Hospital Hamburg, Hamburg, Germany
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University Medical Centre Mannheim
Affiliation as printed
Department of Neurosurgery, University Hospital Mannheim , Mannheim,
Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg , Heidelberg,
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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Affiliation as printed
Department of Neuropathology, University Hospital Magdeburg , Magdeburg,
Department of Neuropathology, University Hospital Magdeburg, Magdeburg, Germany
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Technion – Israel Institute of Technology · Rambam Health Care Campus
Affiliation as printed
Department of Neurosurgery, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion , Haifa,
Department of Neurosurgery, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion, Haifa, Israel
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Tel Aviv University · Tel Aviv Sourasky Medical Center
Affiliation as printed
Department of Neurosurgery, Tel Aviv Medical Center , Tel Aviv,
Sackler School of Medicine, Tel Aviv University , Tel Aviv,
Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, Israel
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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University Medical Centre Mannheim
Affiliation as printed
Department of Neurosurgery, University Hospital Mannheim , Mannheim,
Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany
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University of Zurich · Kantonsspital St. Gallen · University Hospital Zurich
Affiliation as printed
Department of Neurosurgery and Clinical Neuroscience Center, University Hospital and University of Zürich, Zürich, Switzerland
Department of Neurosurgery, Kantonsspital St, Gallen and Medical School St, Gallen, St , Gallen,
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Neurosurgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam , Rotterdam, Netherlands
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Affiliation as printed
Institute of Neuropathology, Faculty of Medicine, University of Freiburg , Freiburg,
Signalling Research Centres BIOSS and CIBSS, University of Freiburg , Freiburg,
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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University of Zurich · University Hospital Zurich
Affiliation as printed
Department of Neurology and Brain Tumour Center, Cancer Center Zürich, University Hospital and University of Zürich , Zürich,
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Justus-Liebig-Universität Gießen
Affiliation as printed
Institute of Neuropathology, Justus-Liebig-University Gießen , Gießen,
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Affiliation as printed
Systems Immunology & Single-Cell Biology, German Cancer Research Center (DKFZ) , Heidelberg,
Systems Immunology & Single-Cell Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Affiliation as printed
Division of Oncology, Department of Medicine I, Medical University of Vienna , Vienna,
Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
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Affiliation as printed
Department of Neurology, University Hospital Tübingen, Eberhard-Karls-University Tübingen , Tübingen,
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg , Heidelberg,
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg , Heidelberg,
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · Hopp Children's Cancer Center Heidelberg
Affiliation as printed
Hopp Children’s Cancer Center Heidelberg (KiTZ) , Heidelberg,
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ) , Heidelberg,
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
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German Cancer Research Center · Hopp Children's Cancer Center Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) , Heidelberg,
Hopp Children’s Cancer Center Heidelberg (KiTZ) , Heidelberg,
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
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German Cancer Research Center · Heidelberg University · National Center for Tumor Diseases
Affiliation as printed
Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University & German Cancer Research Center (DKFZ) , Heidelberg,
Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University & German Cancer Research Center (DKFZ), Heidelberg, Germany
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Sorbonne Université · Pitié-Salpêtrière Hospital
Affiliation as printed
Sorbonne Université and Department of Neurosurgery, Pitié Salpêtrière Hospital , Paris,
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK) , Heidelberg,
Department of Neuropathology, University Hospital Heidelberg , Heidelberg,
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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University of Freiburg · Friedrich-Alexander-Universität Erlangen-Nürnberg · University Medical Center Freiburg
Affiliation as printed
Department of Neurosurgery, Medical Centre-University of Freiburg , Freiburg,
Translational Neurosurgery, Neurosurgical Clinic, Friedrich-Alexander Universität Erlangen-Nürnberg , Erlangen,
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Boston Children's Hospital · Dana-Farber Cancer Institute
Affiliation as printed
Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston,
Division of Hematology/Oncology, Boston Children’s Hospital , Boston,
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, USA
Division of Hematology/Oncology, Boston Children's Hospital, Boston, USA
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Affiliation as printed
Division of AI in Oncology, German Cancer Research Centre (DKFZ) , Heidelberg,
Division of AI in Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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Affiliation as printed
Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg , Augsburg,
Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK) , Heidelberg,
Department of Neuropathology, University Hospital Heidelberg , Heidelberg,
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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