An international study published in Nature reveals how two types of IDH-mutant brain tumors evolve through distinct genetic mechanisms. By comparing tumor samples collected at different time points for each patient, researchers identified characteristic genomic alterations associated with tumor progression and previous treatment exposure. CCA researchers Bart Westerman, Mathilde Kouwenhoven and Pieter Wesseling contributed to this study as part of the international Glioma Longitudinal Analysis (GLASS) Consortium.

Understanding the evolution of gliomas

IDH-mutant astrocytomas and oligodendrogliomas are primary brain tumors that predominantly affect younger adults. Although these tumors may initially respond to treatment, they frequently recur, sometimes with more aggressive characteristics. The molecular changes underlying their progression remain incompletely understood. 

Comparing genomic profiles

To investigate these processes, the GLASS Consortium analyzed tumor samples from 183 patients, including 94 with astrocytoma and 89 with oligodendroglioma. Using whole-genome and whole-exome sequencing, the researchers compared the genomic profiles of tumors obtained during successive surgical procedures. These molecular data were then combined with detailed clinical information, including tumor grade, previous treatments and patient outcomes.

Distinct genomic pathways drive glioma progression

The study revealed distinct patterns of genomic evolution in the two tumor types. In astrocytomas, progression was associated with increasing chromosomal instability, including oncogene amplifications and homozygous deletion of the tumor suppressor locus CDKN2A/B. In contrast, oligodendrogliomas predominantly acquired mutations in specific genes, particularly NOTCH1 and components of the PI3K pathway. These differences were observed independently of treatment exposure. In addition, the researchers identified distinct treatment-associated mutational signatures, suggesting that the genomic consequences of chemotherapy and radiotherapy may differ between glioma subtypes. Several acquired genomic alterations were also associated with poorer patient outcomes although they would need clinical validation. 

International collaboration advances glioma research

The CCA researchers contributed to this international collaborative effort through a KWF supported project called GLASS-NL, where IDH mutated astrocytomas were profiled on the molecular and clinical level. The combination of a large international cohort, extensive genomic characterization and long-term clinical follow-up provides a valuable resource for studying glioma evolution to improve diagnostics and therapeutics.

Publication: Divergent genomic evolution in astrocytomas and oligodendrogliomas. Nature (2026). https://doi.org/10.1038/s41586-026-11150-x