The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen
Recommended Citation
Malta TM, Sabedot TS, Morosini NS, Datta I, Garofano L, Vallentgoed WR, Varn FS, Aldape K, D'Angelo F, Bakas S, Barnholtz-Sloan JS, Gan HK, Hasanain M, Hau AC, Johnson KC, Cazacu S, deCarvalho AC, Khasraw M, Kocakavuk E, Kouwenhoven MCM, Migliozzi S, Niclou SP, Niers JM, Ormond DR, Paek SH, Reifenberger G, Sillevis Smitt PA, Smits M, Stead LF, van den Bent MJ, Van Meir EG, Walenkamp A, Weiss T, Weller M, Westerman BA, Ylstra B, Wesseling P, Lasorella A, French PJ, Poisson LM, Consortium TG, Verhaak RGW, Iavarone A, and Noushmehr H. The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen. Cancer Res 2023; 84(5):741-756.
Document Type
Article
Publication Date
3-4-2024
Publication Title
Cancer research
Abstract
UNLABELLED: Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype.
SIGNIFICANCE: Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.
Medical Subject Headings
Humans; Brain Neoplasms; Epigenesis, Genetic; Epigenomics; Glioma; Isocitrate Dehydrogenase; Mutation; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed ID
38117484
ePublication
ePub ahead of print
Volume
84
Issue
5
First Page
741
Last Page
756
