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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月19日

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  • 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

摘要

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.