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.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
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
UR - https://www.mendeley.com/catalogue/1703f2dd-29f8-3485-a4fc-e0066dd31d7f/
U2 - 10.1038/s43018-025-01023-z
DO - 10.1038/s43018-025-01023-z
M3 - Article
AN - SCOPUS:105013643990
SN - 2662-1347
VL - 6
SP - 1693
EP - 1713
JO - Nature Cancer
JF - Nature Cancer
IS - 10
ER -