Advancing CNS tumor diagnostics with expanded DNA methylation-based classification

Sill M, Schrimpf D, Patel A, Sturm D, Jäger N, Sievers P, Schweizer L, Banan R, Reuss D, Suwala A, Korshunov A, Stichel D, Wefers AK, Hau AC, Boldt H, Harter PN, Abdullaev Z, Benhamida J, Teichmann D, Koch A, Hench J, Frank S, Hasselblatt M, Mansouri S, Díaz de Ståhl T, Serrano J, Ecker J, Selt F, Taylor M, Ramaswamy V, Cavalli F, Berghoff AS, Bison B, Blattner-Johnson M, Buchhalter I, Buslei R, Calaminus G, Dikow N, Dohmen H, Euskirchen P, Fleischhack G, Gajjar A, Gerber NU, Gessi M, Gielen GH, Gnekow A, Gottardo NG, Haberler C, Hamelmann S, Hans V, Hansford JR, Hartmann C, Heppner FL, Driever PH, von Hoff K, Thomale UW, Tippelt S, Frühwald MC, Kramm CM, Schüller U, Schittenhelm J, Schuhmann MU, Stein M, Ketteler P, Ladanyi M, Jabado N, Jones BC, Jones C, Karajannis MA, Ketter R, Kohlhof P, Kordes U, Reinhardt A, Kölsche C, Lamszus K, Lichter P, Maas SL, Mawrin C, Milde T, Mittelbronn M, Monoranu CM, Mueller W, Mynarek M, Northcott PA, Pajtler KW, Paulus W, Perry A, Blümcke I, Plate KH, Platten M, Preusser M, Pietsch T, Prinz M, Reifenberger G, Kristensen BW, Kool M, Hovestadt V, Ellison DW, Jacques TS, Varlet P, Etminan N, Acker T, Weller M, White CL, Witt O, Herold-Mende C, Debus J, Krieg S, Wick W, Snuderl M, Aldape K, Brandner S, Hawkins C, Horbinski C, Thomas C, Wesseling P, von Deimling A, Capper D, Pfister SM, Jones DT, Sahm F (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 44

Pages Range: 340-354.e2

Journal Issue: 2

DOI: 10.1016/j.ccell.2025.11.002

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.

Authors with CRIS profile

Involved external institutions

Hopp-Kindertumorzentrum Heidelberg - KiTZ Germany (DE) Universitätsklinikum Heidelberg Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Universitätsklinikum Münster Germany (DE) Princess Margaret Cancer Centre / Princess Margaret Hospital Canada (CA) New York University (NYU) United States (USA) (US) The Hospital for Sick Children (SickKids) Canada (CA) Institut Curie France (FR) Medizinische Universität Wien Austria (AT) Universität Augsburg Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Klinikum am Bruderwald Germany (DE) Universitätsklinikum Bonn Germany (DE) Universitätsklinikum Heidelberg Germany (DE) Justus-Liebig-Universität Gießen Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universitätsklinikum Essen Germany (DE) St. Jude Children’s Research Hospital United States (USA) (US) Universitäts-Kinderspital Zürich Switzerland (CH) Catholic University of the Sacred Heart / Università Cattolica del Sacro Cuore Italy (IT) Perth Children's Hospital Australia (AU) Memorial Sloan Kettering Cancer Center United States (USA) (US) Universitätsklinikum des Saarlandes (UKS) Germany (DE) Katharinenhospital Stuttgart Germany (DE) Albert-Ludwigs-Universität Freiburg Germany (DE) Universitätsklinikum Regensburg Germany (DE) Odense Universitetshospital (OUH) Denmark (DK) Bayerisches Zentrum für Krebsforschung (BZKF) Germany (DE) National Cancer Institute (NCI) United States (USA) (US) Universitätsspital Basel Switzerland (CH) Karolinska Institute Sweden (SE) Baylor College of Medicine United States (USA) (US) Dietrich-Bonhoeffer-Klinikum Germany (DE) University of Adelaide Australia (AU) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Berliner Institut für Gesundheitsforschung in der Charité / Berlin Institute of Health at Charité (BIH) Germany (DE) Universitätsklinikum Göttingen Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Universitätsklinikum Tübingen Germany (DE) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) The Institute of Cancer Research (ICR) United Kingdom (GB) Ludwig-Maximilians-Universität (LMU) Germany (DE) Leiden University Medical Center Netherlands (NL) Otto-von-Guericke-Universität Magdeburg Germany (DE) University of Luxembourg Luxembourg (LU) Julius-Maximilians-Universität Würzburg Germany (DE) Universität Leipzig Germany (DE) University of California San Francisco (UCSF) United States (USA) (US) Universitätsklinikum Düsseldorf Germany (DE) University of Copenhagen Denmark (DK) Dana-Farber Cancer Institute United States (USA) (US) University of Manchester United Kingdom (GB) Centre hospitalier Sainte-Anne France (FR) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Universitätsspital Zürich (USZ) Switzerland (CH) Victorian Clinical Genetics Services (VCGS) Australia (AU) Ruprecht-Karls-Universität Heidelberg Germany (DE) National Hospital For Neurology and Neurosurgery United Kingdom (GB) Northwestern University United States (USA) (US) Charité - Universitätsmedizin Berlin Germany (DE)

How to cite

APA:

Sill, M., Schrimpf, D., Patel, A., Sturm, D., Jäger, N., Sievers, P.,... Sahm, F. (2026). Advancing CNS tumor diagnostics with expanded DNA methylation-based classification. Cancer Cell, 44(2), 340-354.e2. https://doi.org/10.1016/j.ccell.2025.11.002

MLA:

Sill, Martin, et al. "Advancing CNS tumor diagnostics with expanded DNA methylation-based classification." Cancer Cell 44.2 (2026): 340-354.e2.

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