Advancing CNS tumor diagnostics with expanded DNA methylation-based classification

DNA methylation-based classification is now central to contemporary neuro-oncology, as highlighted by the World Health Organization (WHO) classification of central nervous system (CNS) tumors. We present the Heidelberg CNS Tumor Methylation Classifier version 12.8 (v12.8), trained on 7,495 methylation profiles, which expands recognized entities from 91 classes in version 11 (v11) to 184 subclasses. This expansion is a result of newly identified tumor types discovered through our large online repository and global collaborations, underscoring CNS tumor heterogeneity. The random forest-based classifier achieves 95% subclass-level accuracy, with its well-calibrated probabilistic scores providing a reliable measure of confidence for each classification. Its hierarchical output structure enables interpretation across subclass, class, family, and superfamily levels, thereby supporting clinical decisions at multiple granularities. Comparative analyses demonstrate that v12.8 surpasses previous versions and conventional WHO-based approaches. These advances highlight the improved precision and practical utility of the updated classifier in personalized neuro-oncology.

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Publication Details

Journal
Cancer Cell
Published
2025-12-04
DOI
https://doi.org/10.1016/j.ccell.2025.11.002
Citations
7
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
11.38

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article

Advancing CNS tumor diagnostics with expanded DNA methylation-based classification

Natalie Jaeger, Sybren L. N. Maas, Gerrit H. Gielen, Kristian W. Pajtler et al.
7 citations
Cancer Cell
Glioma Diagnosis and Treatment
11.38
article

Advancing CNS tumor diagnostics with expanded DNA methylation-based classification

Natalie Jaeger, Sybren L. N. Maas, Gerrit H. Gielen, Kristian W. Pajtler, Annika K. Wefers, Martin U. Schuhmann, Sebastian Brandner, Petra Ketteler, Sandro M. Krieg, Matthias A. Karajannis, Theresita Díaz de Ståhl, Damian Stichel, Christof M. Kramm, Craig Horbinski, Christian Johannes Hartmann, Abigail K. Suwala, Ralf Ketter, Guido Reifenberger, Patrick N. Harter, Dominik Sturm, Ann‐Christin Hau, Till Acker, Michael Weller, Nicholas G. Gottardo, Brigitte Bison, Katrin Lamszus, Michel Mittelbronn, Ingmar Blümcke, Michael V. Taylor, Marco Prinz, Philipp Euskirchen, Christian Thomas, Jonas Ecker, Marco Stein, Leonille Schweizer, Henning B. Boldt, Bjarne Winther Kristensen, Martin Hasselblatt, Christel C. Herold‐Mende, Jordan R. Hansford, Gudrun Fleischhack, Daniel Schrimpf, Pablo Hernáiz Driever, Christian Mawrin, Nicola Dikow, Chris Jones, Rolf Buslei, Florence M.G. Cavalli, Till Milde, Nicolas U. Gerber, Andrey Korshunov, Stefan Hamelmann, David Capper, Amar Gajjar, Vijay Ramaswamy, Jens Schittenhelm, David L. Reuss, Rouzbeh Banan, Stefan M. Pfister, Wolf Mueller, Michael C. Frühwald, Zied Abdullaev, Astrid Gnekow, Paul A. Northcott, Marc Ladanyi, Patricia Kohlhof, Philipp Sievers, Jonathan Serrano, Pieter Wesseling, Andreas von Deimling, Arie Perry, Werner Paulus, Marco Gessi, Matthias Preusser, Volkmar Hans, Daniel Teichmann, Uwe Kordes, Felix Sahm, Michael Platten, Jamal K. Benhamida, Cynthia Hawkins, Nada Jabado, Thomas S. Jacques, Ivo Buchhalter, Ulrich Schüller, David W. Ellison, Péter Lichter, Marcel Kool, Volker Hovestadt, Katja von Hoff, Mirjam Blattner-Johnson, Florian Selt, Pascale Varlet, Jürgen Debus, Matija Snuderl, Martin Mynarek, Wolfgang Wick, Areeba Patel, Annekathrin Reinhardt, Christine Haberler, Stephan Tippelt, Frank L. Heppner, Frank Stephan, Sheila Mansouri, Nima Etminan, Martin Sill, Christine L. White, David Jones, Gabriele Calaminus, Torsten Pietsch, Camelia-Maria Monoranu, Barbara C. Jones, Jürgen Hench, Hildegard Dohmen, Arend Koch, Christian Kölsche, Karl H. Plate, Olaf Witt, Ulrich W. Thomale, Ken Aldape
article en
7 citations

Abstract

DNA methylation-based classification is now central to contemporary neuro-oncology, as highlighted by the World Health Organization (WHO) classification of central nervous system (CNS) tumors. We present the Heidelberg CNS Tumor Methylation Classifier version 12.8 (v12.8), trained on 7,495 methylation profiles, which expands recognized entities from 91 classes in version 11 (v11) to 184 subclasses. This expansion is a result of newly identified tumor types discovered through our large online repository and global collaborations, underscoring CNS tumor heterogeneity. The random forest-based classifier achieves 95% subclass-level accuracy, with its well-calibrated probabilistic scores providing a reliable measure of confidence for each classification. Its hierarchical output structure enables interpretation across subclass, class, family, and superfamily levels, thereby supporting clinical decisions at multiple granularities. Comparative analyses demonstrate that v12.8 surpasses previous versions and conventional WHO-based approaches. These advances highlight the improved precision and practical utility of the updated classifier in personalized neuro-oncology.

Cancer CellVol. 44(2)
Università Cattolica del Sacro Cuore (IT), Northwestern University (US), Goethe University Frankfurt (DE), University of Copenhagen (DK), St. Jude Children's Research Hospital (US), Memorial Sloan Kettering Cancer Center (US), University College London Hospitals NHS Foundation Trust (GB), University of Bonn (DE), Technische Hochschule Augsburg (DE), Institute of Cancer Research (GB), Inserm (FR), Universität Hamburg (DE), University of Freiburg (DE), The Kids Research Institute Australia (AU), University of Augsburg (DE), German Cancer Research Center (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), University of Luxembourg (LU), Johannes Gutenberg University Mainz (DE), Justus-Liebig-Universität Gießen (DE), University of Zurich (CH), Heidelberg University (DE), University of Würzburg (DE), Université Paris Sciences et Lettres (FR), University Hospital Bonn (DE), Women's and Children's Hospital (AU), Hospital for Sick Children (CA), Odense University Hospital (DK), McGill University Health Centre (CA), Erasmus MC (NL), University Hospital Augsburg (DE), University Hospital Heidelberg (DE), University Hospital of Basel (CH), Copenhagen University Hospital (DK), Princess Margaret Cancer Centre (CA), Karolinska Institutet (SE), University of Manchester (GB), LMU Klinikum (DE), University Hospital Regensburg (DE), Medizinische Hochschule Hannover (DE), Humboldt-Universität zu Berlin (DE), NYU Langone Health (US), Katharinenhospital (DE), Universitätsklinikum Erlangen (DE), Düsseldorf University Hospital (DE), University Hospital of Zurich (CH), German Cancer Society (DE), University Hospital Münster (DE), University Medical Center Hamburg-Eppendorf (DE), Kinderkrebs-Zentrum Hamburg (DE), Victorian Clinical Genetics Services (AU), National Center for Tumor Diseases (DE), German Center for Infection Research (DE), Universitätsmedizin Göttingen (DE), Hopp Children's Cancer Center Heidelberg (DE), Dana-Farber Cancer Institute (US), Essen University Hospital (DE), Centre Hospitalier Sainte-Anne (FR), University Children's Hospital Tübingen (DE), University Cancer Center Hamburg (DE), University Children's Hospital Zurich (CH), University Hospital Frankfurt (DE), National Cancer Institute (US), Laboratoire National de Santé (LU), Sozialstiftung Bamberg (DE), Center for Cancer Research (US), Comprehensive Cancer Center Erlangen (DE), Erasmus MC Cancer Institute (NL), Children's Cancer Center (US), Amsterdam University Medical Centers (NL), Dietrich Bonhoeffer Klinikum (DE), University Medical Centre Mannheim (DE), Neurological Surgery (US), Frankfurt Cancer Institute (DE), Life & Brain (Germany) (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Heinrich Heine University Düsseldorf (DE), University College London (GB), New York University (US), University of Duisburg-Essen (DE), Medical University of Vienna (AT), Charité - Universitätsmedizin Berlin (DE), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Saarland University (DE), Leipzig University (DE), Otto-von-Guericke-Universität Magdeburg (DE)
Memorial Sloan-Kettering Cancer Center, Deutsches Krebsforschungszentrum, Deutsche Kinderkrebsstiftung, National Institutes of Health, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 1%
Glioma Diagnosis and Treatment
11.38
DOIOpen Access PDFOpenAlex
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