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Supplementary Appendix from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

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posted on 2024-03-04, 22:25 authored by Tathiane M. Malta, Thais S. Sabedot, Natalia S. Morosini, Indrani Datta, Luciano Garofano, Wies 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. Kouwenhoven, Simona 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, Adelheid Woehrer, Allison K Lowman, Ana C deCarvalho, Ana Valeria Castro, Andrea Transou, Andrew R Brodbelt, Ann-Christin Hau, Anna Lasorella, Anna Golebiewska, Annemiek Walenkamp, Annette M Molinaro, Antonio Iavarone, Azzam Ismail, Bart A Westerman, Bauke Ylstra, Christoph Bock, D. Ryan Ormond, Daniel J Brat, Emre Kocakavuk, Erwin G Van Meir, Floris P Barthel, Frederick S Varn, Fulvio D'Angelo, Gaetano Finocchiaro, Ganesh Rao, Gelareh Zadeh, Guido Reifenberger, Ho Keu ngNg, Hoon Kim, Houtan Noushmehr, Hrvoje Miletic, Hui K Gan, Indrani Datta, Jack Rock, James M Snyder, Jason T Huse, Jennifer M Connelly, Jill S Barnholtz-Sloan, Johanna M Niers, John F deGroot, Kadir C Akdemir, Kasthuri S Kannan, Keith L Ligon, Kenneth Aldape, Ketan R Bulsara, Kevin C Johnson, Kristin D Alfaro, Laila M Poisson, Luciano Garofano, Lucy F Stead, MacLean P Nasrallah, Marion Smits, Martin J van den Bent, Mathilde CM Kouwenhoven, Michael Weller, Mohammad Hasanain, Mustafa Khasraw, Peter V Gould, Peter A Sillevis Smitt, Peter S LaViolette, Philip D Tatman, Pieter Wesseling, Pim J French, Rameen Beroukhim, Roel G.W. Verhaak, Simona Migliozzi, Simone P Niclou, Spyridon Bakas, Steven Kalkanis, Sun Ha Paek, Susan C Short, Tabatabai Ghazaleh, Tathiane M Malta, Thais S Sabedot, Tobias Weiss, Tobias Walbert, Ujjwal Baid, Wies Vallentgoed, W. K. Alfred Yung, Roel G.W. Verhaak, Antonio Iavarone, Houtan Noushmehr

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Funding

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

National Institutes of Health (NIH)

Fonds National de la Recherche Luxembourg (FNR)

Jackson Laboratory (JAX)

U.S. Department of Defense (DOD)

Anschutz Medical Campus, University of Colorado (CU AMC)

History

ARTICLE 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. 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.

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    Cancer Research

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    Keywords

    CNS CancersGliomas, GlioblastomasEpigeneticsDNA methylationTumor EvolutionTumor MicroenvironmentImmune cells and the microenvironment

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    CC BY

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