The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen
Authors: Malta Tathiane M. , Sabedot Thais S. , Morosini Natalia S. , Datta Indrani , Garofano Luciano , Vallentgoed Wies , Varn Frederick S. , Aldape Kenneth , D'Angelo Fulvio , Bakas Spyridon , Barnholtz-Sloan Jill S. , Gan Hui K. , Hasanain Mohammad , Hau Ann-Christin , Johnson Kevin C. , Cazacu Simona , deCarvalho Ana C. , Khasraw Mustafa , Kocakavuk Emre , Kouwenhoven Mathilde C.M. , Migliozzi Simona , Niclou Simone P. , Niers Johanna M. , Ormond D. Ryan , Paek Sun Ha , Reifenberger Guido , Sillevis Smitt Peter A. , Smits Marion , Stead Lucy F. , van den Bent Martin J. , Van Meir Erwin G. , Walenkamp Annemiek , Weiss Tobias , Weller Michael , Westerman Bart A. , Ylstra Bauke , Wesseling Pieter , Lasorella Anna , French Pim J. , Poisson Laila M. ,   Consortium The GLASS, Woehrer Adelheid , Lowman Allison K , deCarvalho Ana C , Castro Ana Valeria , Transou Andrea , Brodbelt Andrew R , Hau Ann-Christin , Lasorella Anna , Golebiewska Anna , Walenkamp Annemiek , Molinaro Annette M , Iavarone Antonio , Ismail Azzam , Westerman Bart A , Ylstra Bauke , Bock Christoph , Ormond D. Ryan , Brat Daniel J , Kocakavuk Emre , Van Meir Erwin G , Barthel Floris P , Varn Frederick S , D'Angelo Fulvio , Finocchiaro Gaetano , Rao Ganesh , Zadeh Gelareh , Reifenberger Guido , ngNg Ho Keu , Kim Hoon , Noushmehr Houtan , Miletic Hrvoje , Gan Hui K , Datta Indrani , Rock Jack , Snyder James M , Huse Jason T , Connelly Jennifer M , Barnholtz-Sloan Jill S , Niers Johanna M , deGroot John F , Akdemir Kadir C , Kannan Kasthuri S , Ligon Keith L , Aldape Kenneth , Bulsara Ketan R , Johnson Kevin C , Alfaro Kristin D , Poisson Laila M , Garofano Luciano , Stead Lucy F , Nasrallah MacLean P , Smits Marion , van den Bent Martin J , Kouwenhoven Mathilde CM , Weller Michael , Hasanain Mohammad , Khasraw Mustafa , Gould Peter V , Smitt Peter A Sillevis , LaViolette Peter S , Tatman Philip D , Wesseling Pieter , French Pim J , Beroukhim Rameen , Verhaak Roel G.W. , Migliozzi Simona , Niclou Simone P , Bakas Spyridon , Kalkanis Steven , Paek Sun Ha , Short Susan C , Ghazaleh Tabatabai , Malta Tathiane M , Sabedot Thais S , Weiss Tobias , Walbert Tobias , Baid Ujjwal , Vallentgoed Wies , Yung W. K. Alfred , Verhaak Roel G.W. , Iavarone Antonio , Noushmehr Houtan 
Published: December 2023

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 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.