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

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 feature...

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Main Authors: Vallentgoed, Wies (Author) , Hoogstrate, Youri (Author) , van Garderen, Karin A. (Author) , van Hijfte, Levi (Author) , van Dijk, Erik (Author) , Kouwenhoven, Mathilde C. M. (Author) , Niers, Johanna M. (Author) , Draaisma, Kaspar (Author) , Martin, Ivonne (Author) , de Leng, Wendy W. J. (Author) , Tesileanu, C. Mircea S. (Author) , de Heer, Iris (Author) , Diepeveen, Maud (Author) , Lavrova, Anna (Author) , Eijk, Paul P. (Author) , Bühler, Marcel (Author) , Wick, Wolfgang (Author) , Clement, Paul M. (Author) , Sanson, Marc (Author) , Franceschi, Enrico (Author) , Gorlia, Thierry (Author) , Golfinopoulos, Vassilis (Author) , Weller, Michael (Author) , Weiss, Tobias (Author) , Robe, Pierre A. (Author) , Kros, Johan M. (Author) , Smits, Marion (Author) , van de Wiel, Mark (Author) , Ylstra, Bauke (Author) , Verhaak, Roel G. W. (Author) , van den Bent, Martin J. (Author) , Westerman, Bart A. (Author) , Wesseling, Pieter (Author) , French, Pim J. (Author)
Format: Article (Journal)
Language:English
Published: October 2025
In: Nature cancer
Year: 2025, Volume: 6, Issue: 10, Pages: 1693-1713
ISSN:2662-1347
DOI:10.1038/s43018-025-01023-z
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s43018-025-01023-z
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s43018-025-01023-z
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Author Notes: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
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Summary: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.
Item Description:Online veröffentlicht: 19. August 2025
Gesehen am 21.01.2026
Physical Description:Online Resource
ISSN:2662-1347
DOI:10.1038/s43018-025-01023-z

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