Advancing CNS tumor diagnostics with expanded DNA methylation-based classification

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

doi:10.1016/j.ccell.2025.11.002

Advancing CNS tumor diagnostics with expanded DNA methylation-based classification

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

^*Corresponding author af dette arbejde

3 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Cancer Cell
Vol/bind	44
Udgave nummer	2
Sider (fra-til)	340-354.e2
ISSN	1535-6108
DOI	https://doi.org/10.1016/j.ccell.2025.11.002
Status	Udgivet - 2026

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10.1016/j.ccell.2025.11.002Licens: CC BY

Citationsformater

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, A. K., Hau, A.-C., Boldt, H., Harter, P. N., Abdullaev, Z., Benhamida, J., Teichmann, D., ... 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

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, A-C, 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, SLN, Mawrin, C, Milde, T, Mittelbronn, M, Monoranu, C-M, 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, DTW & Sahm, F 2026, 'Advancing CNS tumor diagnostics with expanded DNA methylation-based classification', Cancer Cell, bind 44, nr. 2, s. 340-354.e2. https://doi.org/10.1016/j.ccell.2025.11.002

@article{5a6fc4fbf06b4d79bde679842cc3beb4,

title = "Advancing CNS tumor diagnostics with expanded DNA methylation-based classification",

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.",

keywords = "artificial intelligence, classification, CNS tumors, DNA methylation, epigenetics, machine learning, MLOps, molecular diagnostics, precision medicine, tumor heterogeneity",

author = "Martin Sill and Daniel Schrimpf and Areeba Patel and Dominik Sturm and Natalie J{\"a}ger and Philipp Sievers and Leonille Schweizer and Rouzbeh Banan and David Reuss and Abigail Suwala and Andrey Korshunov and Damian Stichel and Wefers, {Annika K} and Ann-Christin Hau and Henning Boldt and Harter, {Patrick N} and Zied Abdullaev and Jamal Benhamida and Daniel Teichmann and Arend Koch and J{\"u}rgen Hench and Stephan Frank and Martin Hasselblatt and Sheila Mansouri and {D{\'i}az de St{\aa}hl}, Theresita and Jonathan Serrano and Jonas Ecker and Florian Selt and Michael Taylor and Vijay Ramaswamy and Florence Cavalli and Berghoff, {Anna S} and Brigitte Bison and Mirjam Blattner-Johnson and Ivo Buchhalter and Rolf Buslei and Gabriele Calaminus and Nicola Dikow and Hildegard Dohmen and Philipp Euskirchen and Gudrun Fleischhack and Amar Gajjar and Gerber, {Nicolas U} and Marco Gessi and Gielen, {Gerrit H} and Astrid Gnekow and Gottardo, {Nicholas G} and Christine Haberler and Stefan Hamelmann and Volkmar Hans and Hansford, {Jordan R} and Christian Hartmann and Heppner, {Frank L} and Driever, {Pablo Hernaiz} and {von Hoff}, Katja and Thomale, {Ulrich W} and Stephan Tippelt and Fr{\"u}hwald, {Michael C} and Kramm, {Christof M} and Ulrich Sch{\"u}ller and Jens Schittenhelm and Schuhmann, {Martin U} and Marco Stein and Petra Ketteler and Marc Ladanyi and Nada Jabado and Jones, {Barbara C} and Chris Jones and Karajannis, {Matthias A} and Ralf Ketter and Patricia Kohlhof and Uwe Kordes and Annekathrin Reinhardt and Christian K{\"o}lsche and Katrin Lamszus and Peter Lichter and Maas, {Sybren L N} and Christian Mawrin and Till Milde and Michel Mittelbronn and Camelia-Maria Monoranu and Wolf Mueller and Martin Mynarek and Northcott, {Paul A} and Pajtler, {Kristian W} and Werner Paulus and Arie Perry and Ingmar Bl{\"u}mcke and Plate, {Karl H} and Michael Platten and Matthias Preusser and Torsten Pietsch and Marco Prinz and Guido Reifenberger and Kristensen, {Bjarne W} and Marcel Kool and Volker Hovestadt and Ellison, {David W} and Jacques, {Thomas S} and Pascale Varlet and Nima Etminan and Till Acker and Michael Weller and White, {Christine L} and Olaf Witt and Christel Herold-Mende and J{\"u}rgen Debus and Sandro Krieg and Wolfgang Wick and Matija Snuderl and Ken Aldape and Sebastian Brandner and Cynthia Hawkins and Craig Horbinski and Christian Thomas and Pieter Wesseling and {von Deimling}, Andreas and David Capper and Pfister, {Stefan M} and Jones, {David T W} and Felix Sahm",

year = "2026",

doi = "10.1016/j.ccell.2025.11.002",

language = "English",

volume = "44",

pages = "340--354.e2",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Advancing CNS tumor diagnostics with expanded DNA methylation-based classification

AU - Sill, Martin

AU - Schrimpf, Daniel

AU - Patel, Areeba

AU - Sturm, Dominik

AU - Jäger, Natalie

AU - Sievers, Philipp

AU - Schweizer, Leonille

AU - Banan, Rouzbeh

AU - Reuss, David

AU - Suwala, Abigail

AU - Korshunov, Andrey

AU - Stichel, Damian

AU - Wefers, Annika K

AU - Hau, Ann-Christin

AU - Boldt, Henning

AU - Harter, Patrick N

AU - Abdullaev, Zied

AU - Benhamida, Jamal

AU - Teichmann, Daniel

AU - Koch, Arend

AU - Hench, Jürgen

AU - Frank, Stephan

AU - Hasselblatt, Martin

AU - Mansouri, Sheila

AU - Díaz de Ståhl, Theresita

AU - Serrano, Jonathan

AU - Ecker, Jonas

AU - Selt, Florian

AU - Taylor, Michael

AU - Ramaswamy, Vijay

AU - Cavalli, Florence

AU - Berghoff, Anna S

AU - Bison, Brigitte

AU - Blattner-Johnson, Mirjam

AU - Buchhalter, Ivo

AU - Buslei, Rolf

AU - Calaminus, Gabriele

AU - Dikow, Nicola

AU - Dohmen, Hildegard

AU - Euskirchen, Philipp

AU - Fleischhack, Gudrun

AU - Gajjar, Amar

AU - Gerber, Nicolas U

AU - Gessi, Marco

AU - Gielen, Gerrit H

AU - Gnekow, Astrid

AU - Gottardo, Nicholas G

AU - Haberler, Christine

AU - Hamelmann, Stefan

AU - Hans, Volkmar

AU - Hansford, Jordan R

AU - Hartmann, Christian

AU - Heppner, Frank L

AU - Driever, Pablo Hernaiz

AU - von Hoff, Katja

AU - Thomale, Ulrich W

AU - Tippelt, Stephan

AU - Frühwald, Michael C

AU - Kramm, Christof M

AU - Schüller, Ulrich

AU - Schittenhelm, Jens

AU - Schuhmann, Martin U

AU - Stein, Marco

AU - Ketteler, Petra

AU - Ladanyi, Marc

AU - Jabado, Nada

AU - Jones, Barbara C

AU - Jones, Chris

AU - Karajannis, Matthias A

AU - Ketter, Ralf

AU - Kohlhof, Patricia

AU - Kordes, Uwe

AU - Reinhardt, Annekathrin

AU - Kölsche, Christian

AU - Lamszus, Katrin

AU - Lichter, Peter

AU - Maas, Sybren L N

AU - Mawrin, Christian

AU - Milde, Till

AU - Mittelbronn, Michel

AU - Monoranu, Camelia-Maria

AU - Mueller, Wolf

AU - Mynarek, Martin

AU - Northcott, Paul A

AU - Pajtler, Kristian W

AU - Paulus, Werner

AU - Perry, Arie

AU - Blümcke, Ingmar

AU - Plate, Karl H

AU - Platten, Michael

AU - Preusser, Matthias

AU - Pietsch, Torsten

AU - Prinz, Marco

AU - Reifenberger, Guido

AU - Kristensen, Bjarne W

AU - Kool, Marcel

AU - Hovestadt, Volker

AU - Ellison, David W

AU - Jacques, Thomas S

AU - Varlet, Pascale

AU - Etminan, Nima

AU - Acker, Till

AU - Weller, Michael

AU - White, Christine L

AU - Witt, Olaf

AU - Herold-Mende, Christel

AU - Debus, Jürgen

AU - Krieg, Sandro

AU - Wick, Wolfgang

AU - Snuderl, Matija

AU - Aldape, Ken

AU - Brandner, Sebastian

AU - Hawkins, Cynthia

AU - Horbinski, Craig

AU - Thomas, Christian

AU - Wesseling, Pieter

AU - von Deimling, Andreas

AU - Capper, David

AU - Pfister, Stefan M

AU - Jones, David T W

AU - Sahm, Felix

PY - 2026

Y1 - 2026

N2 - 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.

AB - 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.

KW - artificial intelligence

KW - classification

KW - CNS tumors

KW - DNA methylation

KW - epigenetics

KW - machine learning

KW - MLOps

KW - molecular diagnostics

KW - precision medicine

KW - tumor heterogeneity

U2 - 10.1016/j.ccell.2025.11.002

DO - 10.1016/j.ccell.2025.11.002

M3 - Journal article

C2 - 41349541

SN - 1535-6108

VL - 44

SP - 340-354.e2

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Advancing CNS tumor diagnostics with expanded DNA methylation-based classification

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