The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen

Tathiane M Malta, Thais S Sabedot, Natalia S Morosini, Indrani Datta, Luciano Garofano, Wies R Vallentgoed, Frederick S Varn, Kenneth Aldape, Fulvio D'Angelo, Spyridon Bakas, Jill S Barnholtz-Sloan, Hui K Gan, Mohammad Hasanain, Ann-Christin Hau, Kevin C Johnson, Simona Cazacu, Ana C deCarvalho, Mustafa Khasraw, Emre Kocakavuk, Mathilde C M KouwenhovenSimona Migliozzi, Simone P Niclou, Johanna M Niers, D Ryan Ormond, Sun Ha Paek, Guido Reifenberger, Peter A Sillevis Smitt, Marion Smits, Lucy F Stead, Martin J van den Bent, Erwin G Van Meir, Annemiek Walenkamp, Tobias Weiss, Michael Weller, Bart A Westerman, Bauke Ylstra, Pieter Wesseling, Anna Lasorella, Pim J French, Laila M Poisson, The Glass Consortium, Roel G W Verhaak, Antonio Iavarone, Houtan Noushmehr*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 histological 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 neo-angiogenesis 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 towards an IDHwt-like phenotype.

Original languageEnglish
JournalCancer Research
DOIs
Publication statusE-pub ahead of print - 20 Dec 2023

Fingerprint

Dive into the research topics of 'The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen'. Together they form a unique fingerprint.

Cite this