Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling

Wies R Vallentgoed; Youri Hoogstrate; Karin A van Garderen; Levi van Hijfte; Erik van Dijk; Mathilde C M Kouwenhoven; Johanna M Niers; Kaspar Draaisma; Ivonne Martin; Wendy W J de Leng; C Mircea S Tesileanu; Iris de Heer; Maud Diepeveen; Anna Lavrova; Paul P Eijk; Marcel Bühler; Wolfgang Wick; Paul M Clement; Marc Sanson; Enrico Franceschi; Thierry Gorlia; Vassilis Golfinopoulos; Michael Weller; Tobias Weiss; Pierre A Robe; Johan M Kros; Marion Smits; Mark van de Wiel; Bauke Ylstra; Roel G W Verhaak; Martin J van den Bent; Bart A Westerman; Pieter Wesseling; Pim J French

doi:10.1038/s43018-025-01023-z

Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling

Wies R Vallentgoed^*
, Youri Hoogstrate
, Karin A van Garderen
, Levi van Hijfte
, Erik van Dijk
, Mathilde C M Kouwenhoven
, Johanna M Niers
, Kaspar Draaisma
, Ivonne Martin
, Wendy W J de Leng
, C Mircea S Tesileanu
, Iris de Heer
, Maud Diepeveen
, Anna Lavrova
, Paul P Eijk
, Marcel Bühler
, Wolfgang Wick
, Paul M Clement
, Marc Sanson
, Enrico Franceschi

Thierry Gorlia, Vassilis Golfinopoulos, Michael Weller, Tobias Weiss, Pierre A Robe, Johan M Kros, Marion Smits, Mark van de Wiel, Bauke Ylstra, Roel G W Verhaak, Martin J van den Bent, Bart A Westerman, Pieter Wesseling, Pim J French^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The evolutionary processes that drive malignant progression of IDH-mutant astrocytomas remain unclear. Here, we performed multiomics on matched initial and recurrent tumor samples from a cohort of 105 patients and overlaid the data with detailed clinical annotation. We identified overlapping features associated with malignant progression that are derived from three molecular mechanisms: cell cycling, tumor cell (de)differentiation and remodeling of the extracellular matrix. Together, they provide a rationale of the underlying biology of tumor malignancy. DNA methylation levels decreased over time, predominantly in tumors with malignant transformation, and co-occurred with poor prognostic genetic events. We identified a DNA methylation-based signature strongly associated with survival, which allows objective, molecular-based grading of IDH-mutant astrocytomas to aid clinical decision making. Our findings were validated on large, independent cohorts of IDH-mutant astrocytoma samples. Lastly, in this retrospective study, we found little effect of radiotherapy or chemotherapy on the molecular features associated with malignant progression.

Original language	English
Pages (from-to)	1693-1713
Number of pages	21
Journal	Nature Cancer
Volume	6
Issue number	10
Early online date	19 Aug 2025
DOIs	https://doi.org/10.1038/s43018-025-01023-z
Publication status	Published - Oct 2025

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Vallentgoed, W. R., Hoogstrate, Y., van Garderen, K. A., van Hijfte, L., van Dijk, E., Kouwenhoven, M. C. M., Niers, J. M., Draaisma, K., Martin, I., de Leng, W. W. J., Tesileanu, C. M. S., de Heer, I., Diepeveen, M., Lavrova, A., Eijk, P. P., Bühler, M., Wick, W., Clement, P. M., Sanson, M., ... French, P. J. (2025). Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling. Nature Cancer, 6(10), 1693-1713. https://doi.org/10.1038/s43018-025-01023-z

@article{86d10428acaa4468ae40e3ffa3e3e831,

title = "Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling",

abstract = "The evolutionary processes that drive malignant progression of IDH-mutant astrocytomas remain unclear. Here, we performed multiomics on matched initial and recurrent tumor samples from a cohort of 105 patients and overlaid the data with detailed clinical annotation. We identified overlapping features associated with malignant progression that are derived from three molecular mechanisms: cell cycling, tumor cell (de)differentiation and remodeling of the extracellular matrix. Together, they provide a rationale of the underlying biology of tumor malignancy. DNA methylation levels decreased over time, predominantly in tumors with malignant transformation, and co-occurred with poor prognostic genetic events. We identified a DNA methylation-based signature strongly associated with survival, which allows objective, molecular-based grading of IDH-mutant astrocytomas to aid clinical decision making. Our findings were validated on large, independent cohorts of IDH-mutant astrocytoma samples. Lastly, in this retrospective study, we found little effect of radiotherapy or chemotherapy on the molecular features associated with malignant progression.",

author = "Vallentgoed, \{Wies R\} and Youri Hoogstrate and \{van Garderen\}, \{Karin A\} and \{van Hijfte\}, Levi and \{van Dijk\}, Erik and Kouwenhoven, \{Mathilde C M\} and Niers, \{Johanna M\} and Kaspar Draaisma and Ivonne Martin and \{de Leng\}, \{Wendy W J\} and Tesileanu, \{C Mircea S\} and \{de Heer\}, Iris and Maud Diepeveen and Anna Lavrova and Eijk, \{Paul P\} and Marcel B{\"u}hler and Wolfgang Wick and Clement, \{Paul M\} and Marc Sanson and Enrico Franceschi and Thierry Gorlia and Vassilis Golfinopoulos and Michael Weller and Tobias Weiss and Robe, \{Pierre A\} and Kros, \{Johan M\} and Marion Smits and \{van de Wiel\}, Mark and Bauke Ylstra and Verhaak, \{Roel G W\} and \{van den Bent\}, \{Martin J\} and Westerman, \{Bart A\} and Pieter Wesseling and French, \{Pim J\}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = oct,

doi = "10.1038/s43018-025-01023-z",

language = "English",

volume = "6",

pages = "1693--1713",

journal = "Nature Cancer",

publisher = "Nature Research",

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Vallentgoed, WR, Hoogstrate, Y, van Garderen, KA, van Hijfte, L, van Dijk, E, Kouwenhoven, MCM, Niers, JM, Draaisma, K, Martin, I, de Leng, WWJ, Tesileanu, CMS, de Heer, I, Diepeveen, M, Lavrova, A, Eijk, PP, Bühler, M, Wick, W, Clement, PM, Sanson, M, Franceschi, E, Gorlia, T, Golfinopoulos, V, Weller, M, Weiss, T, Robe, PA, Kros, JM, Smits, M, van de Wiel, M, Ylstra, B, Verhaak, RGW, van den Bent, MJ, Westerman, BA, Wesseling, P & French, PJ 2025, 'Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling', Nature Cancer, vol. 6, no. 10, pp. 1693-1713. https://doi.org/10.1038/s43018-025-01023-z

TY - JOUR

T1 - Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling

AU - Vallentgoed, Wies R

AU - Hoogstrate, Youri

AU - van Garderen, Karin A

AU - van Hijfte, Levi

AU - van Dijk, Erik

AU - Kouwenhoven, Mathilde C M

AU - Niers, Johanna M

AU - Draaisma, Kaspar

AU - Martin, Ivonne

AU - de Leng, Wendy W J

AU - Tesileanu, C Mircea S

AU - de Heer, Iris

AU - Diepeveen, Maud

AU - Lavrova, Anna

AU - Eijk, Paul P

AU - Bühler, Marcel

AU - Wick, Wolfgang

AU - Clement, Paul M

AU - Sanson, Marc

AU - Franceschi, Enrico

AU - Gorlia, Thierry

AU - Golfinopoulos, Vassilis

AU - Weller, Michael

AU - Weiss, Tobias

AU - Robe, Pierre A

AU - Kros, Johan M

AU - Smits, Marion

AU - van de Wiel, Mark

AU - Ylstra, Bauke

AU - Verhaak, Roel G W

AU - van den Bent, Martin J

AU - Westerman, Bart A

AU - Wesseling, Pieter

AU - French, Pim J

PY - 2025/10

Y1 - 2025/10

N2 - The evolutionary processes that drive malignant progression of IDH-mutant astrocytomas remain unclear. Here, we performed multiomics on matched initial and recurrent tumor samples from a cohort of 105 patients and overlaid the data with detailed clinical annotation. We identified overlapping features associated with malignant progression that are derived from three molecular mechanisms: cell cycling, tumor cell (de)differentiation and remodeling of the extracellular matrix. Together, they provide a rationale of the underlying biology of tumor malignancy. DNA methylation levels decreased over time, predominantly in tumors with malignant transformation, and co-occurred with poor prognostic genetic events. We identified a DNA methylation-based signature strongly associated with survival, which allows objective, molecular-based grading of IDH-mutant astrocytomas to aid clinical decision making. Our findings were validated on large, independent cohorts of IDH-mutant astrocytoma samples. Lastly, in this retrospective study, we found little effect of radiotherapy or chemotherapy on the molecular features associated with malignant progression.

AB - The evolutionary processes that drive malignant progression of IDH-mutant astrocytomas remain unclear. Here, we performed multiomics on matched initial and recurrent tumor samples from a cohort of 105 patients and overlaid the data with detailed clinical annotation. We identified overlapping features associated with malignant progression that are derived from three molecular mechanisms: cell cycling, tumor cell (de)differentiation and remodeling of the extracellular matrix. Together, they provide a rationale of the underlying biology of tumor malignancy. DNA methylation levels decreased over time, predominantly in tumors with malignant transformation, and co-occurred with poor prognostic genetic events. We identified a DNA methylation-based signature strongly associated with survival, which allows objective, molecular-based grading of IDH-mutant astrocytomas to aid clinical decision making. Our findings were validated on large, independent cohorts of IDH-mutant astrocytoma samples. Lastly, in this retrospective study, we found little effect of radiotherapy or chemotherapy on the molecular features associated with malignant progression.

UR - https://www.scopus.com/pages/publications/105013643990

U2 - 10.1038/s43018-025-01023-z

DO - 10.1038/s43018-025-01023-z

M3 - Article

C2 - 40830455

VL - 6

SP - 1693

EP - 1713

JO - Nature Cancer

JF - Nature Cancer

IS - 10

ER -

Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling

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