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 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; Consortium The GLASS

doi:10.1158/0008-5472.CAN-23-2093

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 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, Consortium The GLASS

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	741-756
Number of pages	16
Journal	Cancer research
Volume	84
Issue number	5
DOIs	https://doi.org/10.1158/0008-5472.CAN-23-2093
Publication status	Published - 1 Mar 2024

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Malta, T. M., Sabedot, T. S., Morosini, N. S., Datta, I., Garofano, L., Vallentgoed, W., Varn, F. S., Aldape, K., D'Angelo, F., Bakas, S., Barnholtz-Sloan, J. S., Gan, H. K., Hasanain, M., Hau, A.-C., Johnson, K. C., Cazacu, S., deCarvalho, A. C., Khasraw, M., Kocakavuk, E., ... Consortium The GLASS (2024). The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen. Cancer research, 84(5), 741-756. https://doi.org/10.1158/0008-5472.CAN-23-2093

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title = "The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors.",

year = "2024",

month = mar,

day = "1",

doi = "10.1158/0008-5472.CAN-23-2093",

language = "English",

volume = "84",

pages = "741--756",

journal = "Cancer research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "5",

}

Malta, TM, Sabedot, TS, Morosini, NS, Datta, I, Garofano, L, Vallentgoed, W, Varn, FS, Aldape, K, D'Angelo, F, Bakas, S, Barnholtz-Sloan, JS, Gan, HK, Hasanain, M, Hau, A-C, 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 The GLASS 2024, 'The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen', Cancer research, vol. 84, no. 5, pp. 741-756. https://doi.org/10.1158/0008-5472.CAN-23-2093

TY - JOUR

T1 - The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

AU - Malta, Tathiane M.

AU - Sabedot, Thais S.

AU - Morosini, Natalia S.

AU - Datta, Indrani

AU - Garofano, Luciano

AU - Vallentgoed, Wies

AU - Varn, Frederick S.

AU - Aldape, Kenneth

AU - D'Angelo, Fulvio

AU - Bakas, Spyridon

AU - Barnholtz-Sloan, Jill S.

AU - Gan, Hui K.

AU - Hasanain, Mohammad

AU - Hau, Ann-Christin

AU - Johnson, Kevin C.

AU - Cazacu, Simona

AU - deCarvalho, Ana C.

AU - Khasraw, Mustafa

AU - Kocakavuk, Emre

AU - Kouwenhoven, Mathilde C. M.

AU - Migliozzi, Simona

AU - Niclou, Simone P.

AU - Niers, Johanna M.

AU - Ormond, D. Ryan

AU - Paek, Sun Ha

AU - Reifenberger, Guido

AU - Sillevis Smitt, Peter A.

AU - Smits, Marion

AU - Stead, Lucy F.

AU - van den Bent, Martin J.

AU - van Meir, Erwin G.

AU - Walenkamp, Annemiek

AU - Weiss, Tobias

AU - Weller, Michael

AU - Westerman, Bart A.

AU - Ylstra, Bauke

AU - Wesseling, Pieter

AU - Lasorella, Anna

AU - French, Pim J.

AU - Poisson, Laila M.

AU - Consortium The GLASS

AU - Verhaak, Roel G. W.

AU - Iavarone, Antonio

AU - Noushmehr, Houtan

PY - 2024/3/1

Y1 - 2024/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85186954374&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-23-2093

DO - 10.1158/0008-5472.CAN-23-2093

M3 - Article

C2 - 38117484

SN - 0008-5472

VL - 84

SP - 741

EP - 756

JO - Cancer research

JF - Cancer research

IS - 5

ER -

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

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