Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

C. Mircea S. Tesileanu; Wies R. Vallentgoed; Marc Sanson; Walter Taal; Paul M. Clement; Wolfgang Wick; Alba Ariela Brandes; Jean Francais Baurain; Olivier L. Chinot; Helen Wheeler; Sanjeev Gill; Matthew Griffin; Leland Rogers; Roberta Rudà; Michael Weller; Catherine McBain; Jaap Reijneveld; Roelien H. Enting; Francesca Caparrotti; Thierry Lesimple; Susan Clenton; Anja Gijtenbeek; Elizabeth Lim; Filip de Vos; Paul J. Mulholland; Martin J.B. Taphoorn; Iris de Heer; Youri Hoogstrate; Maurice de Wit; Lorenzo Boggiani; Sanne Venneker; Jan Oosting; Judith V.M.G. Bovée; Sara Erridge; Michael A. Vogelbaum; Anna K. Nowak; Warren P. Mason; Johan M. Kros; Pieter Wesseling; Ken Aldape; Robert B. Jenkins; Hendrikus J. Dubbink; Brigitta Baumert; Vassilis Golfinopoulos; Thierry Gorlia; Martin van den Bent; Pim J. French

doi:10.1007/s00401-021-02291-6

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

C. Mircea S. Tesileanu, Wies R. Vallentgoed, Marc Sanson, Walter Taal, Paul M. Clement, Wolfgang Wick, Alba Ariela Brandes, Jean Francais Baurain, Olivier L. Chinot, Helen Wheeler, Sanjeev Gill, Matthew Griffin, Leland Rogers, Roberta Rudà, Michael Weller, Catherine McBain, Jaap Reijneveld, Roelien H. Enting, Francesca Caparrotti, Thierry LesimpleSusan Clenton, Anja Gijtenbeek, Elizabeth Lim, Filip de Vos, Paul J. Mulholland, Martin J.B. Taphoorn, Iris de Heer, Youri Hoogstrate, Maurice de Wit, Lorenzo Boggiani, Sanne Venneker, Jan Oosting, Judith V.M.G. Bovée, Sara Erridge, Michael A. Vogelbaum, Anna K. Nowak, Warren P. Mason, Johan M. Kros, Pieter Wesseling, Ken Aldape, Robert B. Jenkins, Hendrikus J. Dubbink, Brigitta Baumert, Vassilis Golfinopoulos, Thierry Gorlia, Martin van den Bent, Pim J. French

Laboratory Medicine and Pathology

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

2 Scopus citations

Abstract

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1^R132H mutations. Patients harbouring IDH1^R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1^R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1^R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

Original language	English (US)
Pages (from-to)	945-957
Number of pages	13
Journal	Acta neuropathologica
Volume	141
Issue number	6
DOIs	https://doi.org/10.1007/s00401-021-02291-6
State	Published - Jun 2021

Keywords

Astrocytoma
Gene expression
Genome-wide DNA methylation
IDH1
IDH2

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

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10.1007/s00401-021-02291-6

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Tesileanu, C. M. S., Vallentgoed, W. R., Sanson, M., Taal, W., Clement, P. M., Wick, W., Brandes, A. A., Baurain, J. F., Chinot, O. L., Wheeler, H., Gill, S., Griffin, M., Rogers, L., Rudà, R., Weller, M., McBain, C., Reijneveld, J., Enting, R. H., Caparrotti, F., ... French, P. J. (2021). Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations. Acta neuropathologica, 141(6), 945-957. https://doi.org/10.1007/s00401-021-02291-6

Tesileanu, CMS, Vallentgoed, WR, Sanson, M, Taal, W, Clement, PM, Wick, W, Brandes, AA, Baurain, JF, Chinot, OL, Wheeler, H, Gill, S, Griffin, M, Rogers, L, Rudà, R, Weller, M, McBain, C, Reijneveld, J, Enting, RH, Caparrotti, F, Lesimple, T, Clenton, S, Gijtenbeek, A, Lim, E, de Vos, F, Mulholland, PJ, Taphoorn, MJB, de Heer, I, Hoogstrate, Y, de Wit, M, Boggiani, L, Venneker, S, Oosting, J, Bovée, JVMG, Erridge, S, Vogelbaum, MA, Nowak, AK, Mason, WP, Kros, JM, Wesseling, P, Aldape, K, Jenkins, RB, Dubbink, HJ, Baumert, B, Golfinopoulos, V, Gorlia, T, van den Bent, M & French, PJ 2021, 'Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations', Acta neuropathologica, vol. 141, no. 6, pp. 945-957. https://doi.org/10.1007/s00401-021-02291-6

@article{87f3ee9e859049499a880d7a9fda378e,

title = "Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations",

abstract = "Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.",

keywords = "Astrocytoma, Gene expression, Genome-wide DNA methylation, IDH1, IDH2",

author = "Tesileanu, {C. Mircea S.} and Vallentgoed, {Wies R.} and Marc Sanson and Walter Taal and Clement, {Paul M.} and Wolfgang Wick and Brandes, {Alba Ariela} and Baurain, {Jean Francais} and Chinot, {Olivier L.} and Helen Wheeler and Sanjeev Gill and Matthew Griffin and Leland Rogers and Roberta Rud{\`a} and Michael Weller and Catherine McBain and Jaap Reijneveld and Enting, {Roelien H.} and Francesca Caparrotti and Thierry Lesimple and Susan Clenton and Anja Gijtenbeek and Elizabeth Lim and {de Vos}, Filip and Mulholland, {Paul J.} and Taphoorn, {Martin J.B.} and {de Heer}, Iris and Youri Hoogstrate and {de Wit}, Maurice and Lorenzo Boggiani and Sanne Venneker and Jan Oosting and Bov{\'e}e, {Judith V.M.G.} and Sara Erridge and Vogelbaum, {Michael A.} and Nowak, {Anna K.} and Mason, {Warren P.} and Kros, {Johan M.} and Pieter Wesseling and Ken Aldape and Jenkins, {Robert B.} and Dubbink, {Hendrikus J.} and Brigitta Baumert and Vassilis Golfinopoulos and Thierry Gorlia and {van den Bent}, Martin and French, {Pim J.}",

note = "Funding Information: The CATNON study was funded by Merck, Sharp and Dohme, and the Brain Tumor Group. The genome-wide DNA methylation profiles study was funded by Grant GN-000577 from The Brain Tumour Charity, grant 10685 from the Dutch Cancer Society, financial support from the Vereniging Heino {\textquoteright}Strijd van Salland{\textquoteright}, and Grant CA170278 from the United States Department of Defence. The authors thank the European Organization for Research and Treatment of Cancer for permission to use the data from EORTC studies 26053/22054 (CATNON) and 26091 (TAVAREC) for this research. Funding Information: MS reports research grants from Astra-Zeneca, travel grant from Abbvie, personal fees from Genenta, outside the submitted work, PM reports support to attend conferences from BMS and an award towards an investigator-initiated study from BMS. BB reports a MERCK grant for the EORTC22033 lGG study. MAV has indirect equity interest and royalty rights from Infuseon Therapeutics, Inc. He has received honoraria from Tocagen, Cellinta, and Celgene. None of these interests overlaps with the research presented in this manuscript. Wolfgang Wick receives trial funding from Apogenix, Boehringer Ingelheim, Pfizer and Roche to the institution. He serves on advisory boards for Agios, Bayer, MSD, Novartis, Roche with compensation paid to the institution. MJvdB reports grants from Dutch Cancer Foundation, grants from Brain Tumor Charity, grants from Strijd van Salland, grants from MSD formerly Schering Plough, during the conduct of the study; personal fees from Carthera, personal fees from Nerviano, personal fees from Bayer, personal fees from Celgene, personal fees from Agios, personal fees from Abbvie, personal fees from Karyopharm, personal fees from Boston Pharmaceuticals, personal fees from Genenta, outside the submitted work. AN received research funding from Astra Zeneca, and Douglas Pharmaceuticals, consultancies for Bayer, Roche, Boehringer Ingelheim, MSD, Douglas Pharmaceuticals, Pharmabcine, Atara biotherapeutics, Trizell and Seagen. MW has received research grants from Abbvie, Adastra, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure and Quercis, and honoraria for lectures or advisory board participation or consulting from Abbvie, Adastra, Basilea, Bristol Meyer Squibb (BMS), Celgene, Medac, Merck, Sharp & Dohme (MSD), Merck (EMD), Nerviano Medical Sciences, Novartis, Orbus, Philogen, Roche and Tocagen. FdV reports support from AbbVie, Bioclin Therapeutics, BMS, GSK, Novartis, Octimed Oncology and Vaximm, outside the submitted work. PC reports support from BMS, AbbVie, Merck Serono, MSD, Vifor Pharma, Daiichi Sankyo, Leo Pharma and Astra Zeneca, outside the submitted work. PJF reports grants from Dutch Cancer Foundation, the Brain Tumor Charity, the Strijd van Salland, de Westlandse ride and Hersentumorfonds, outside submitted work. Other authors report no conflict of interest. Funding Information: The CATNON study was funded by Merck, Sharp and Dohme, and the Brain Tumor Group. The genome-wide DNA methylation profiles study was funded by Grant GN-000577 from The Brain Tumour Charity, grant 10685 from the Dutch Cancer Society, financial support from the Vereniging Heino {\textquoteright}Strijd van Salland{\textquoteright}, and Grant CA170278 from the United States Department of Defence. The authors thank the European Organization for Research and Treatment of Cancer for permission to use the data from EORTC studies 26053/22054 (CATNON) and 26091 (TAVAREC) for this research. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jun,

doi = "10.1007/s00401-021-02291-6",

language = "English (US)",

volume = "141",

pages = "945--957",

journal = "Acta Neuropathologica",

issn = "0001-6322",

publisher = "Springer Verlag",

number = "6",

}

TY - JOUR

T1 - Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

AU - Tesileanu, C. Mircea S.

AU - Vallentgoed, Wies R.

AU - Sanson, Marc

AU - Taal, Walter

AU - Clement, Paul M.

AU - Wick, Wolfgang

AU - Brandes, Alba Ariela

AU - Baurain, Jean Francais

AU - Chinot, Olivier L.

AU - Wheeler, Helen

AU - Gill, Sanjeev

AU - Griffin, Matthew

AU - Rogers, Leland

AU - Rudà, Roberta

AU - Weller, Michael

AU - McBain, Catherine

AU - Reijneveld, Jaap

AU - Enting, Roelien H.

AU - Caparrotti, Francesca

AU - Lesimple, Thierry

AU - Clenton, Susan

AU - Gijtenbeek, Anja

AU - Lim, Elizabeth

AU - de Vos, Filip

AU - Mulholland, Paul J.

AU - Taphoorn, Martin J.B.

AU - de Heer, Iris

AU - Hoogstrate, Youri

AU - de Wit, Maurice

AU - Boggiani, Lorenzo

AU - Venneker, Sanne

AU - Oosting, Jan

AU - Bovée, Judith V.M.G.

AU - Erridge, Sara

AU - Vogelbaum, Michael A.

AU - Nowak, Anna K.

AU - Mason, Warren P.

AU - Kros, Johan M.

AU - Wesseling, Pieter

AU - Aldape, Ken

AU - Jenkins, Robert B.

AU - Dubbink, Hendrikus J.

AU - Baumert, Brigitta

AU - Golfinopoulos, Vassilis

AU - Gorlia, Thierry

AU - van den Bent, Martin

AU - French, Pim J.

N1 - Funding Information: The CATNON study was funded by Merck, Sharp and Dohme, and the Brain Tumor Group. The genome-wide DNA methylation profiles study was funded by Grant GN-000577 from The Brain Tumour Charity, grant 10685 from the Dutch Cancer Society, financial support from the Vereniging Heino ’Strijd van Salland’, and Grant CA170278 from the United States Department of Defence. The authors thank the European Organization for Research and Treatment of Cancer for permission to use the data from EORTC studies 26053/22054 (CATNON) and 26091 (TAVAREC) for this research. Funding Information: MS reports research grants from Astra-Zeneca, travel grant from Abbvie, personal fees from Genenta, outside the submitted work, PM reports support to attend conferences from BMS and an award towards an investigator-initiated study from BMS. BB reports a MERCK grant for the EORTC22033 lGG study. MAV has indirect equity interest and royalty rights from Infuseon Therapeutics, Inc. He has received honoraria from Tocagen, Cellinta, and Celgene. None of these interests overlaps with the research presented in this manuscript. Wolfgang Wick receives trial funding from Apogenix, Boehringer Ingelheim, Pfizer and Roche to the institution. He serves on advisory boards for Agios, Bayer, MSD, Novartis, Roche with compensation paid to the institution. MJvdB reports grants from Dutch Cancer Foundation, grants from Brain Tumor Charity, grants from Strijd van Salland, grants from MSD formerly Schering Plough, during the conduct of the study; personal fees from Carthera, personal fees from Nerviano, personal fees from Bayer, personal fees from Celgene, personal fees from Agios, personal fees from Abbvie, personal fees from Karyopharm, personal fees from Boston Pharmaceuticals, personal fees from Genenta, outside the submitted work. AN received research funding from Astra Zeneca, and Douglas Pharmaceuticals, consultancies for Bayer, Roche, Boehringer Ingelheim, MSD, Douglas Pharmaceuticals, Pharmabcine, Atara biotherapeutics, Trizell and Seagen. MW has received research grants from Abbvie, Adastra, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure and Quercis, and honoraria for lectures or advisory board participation or consulting from Abbvie, Adastra, Basilea, Bristol Meyer Squibb (BMS), Celgene, Medac, Merck, Sharp & Dohme (MSD), Merck (EMD), Nerviano Medical Sciences, Novartis, Orbus, Philogen, Roche and Tocagen. FdV reports support from AbbVie, Bioclin Therapeutics, BMS, GSK, Novartis, Octimed Oncology and Vaximm, outside the submitted work. PC reports support from BMS, AbbVie, Merck Serono, MSD, Vifor Pharma, Daiichi Sankyo, Leo Pharma and Astra Zeneca, outside the submitted work. PJF reports grants from Dutch Cancer Foundation, the Brain Tumor Charity, the Strijd van Salland, de Westlandse ride and Hersentumorfonds, outside submitted work. Other authors report no conflict of interest. Funding Information: The CATNON study was funded by Merck, Sharp and Dohme, and the Brain Tumor Group. The genome-wide DNA methylation profiles study was funded by Grant GN-000577 from The Brain Tumour Charity, grant 10685 from the Dutch Cancer Society, financial support from the Vereniging Heino ’Strijd van Salland’, and Grant CA170278 from the United States Department of Defence. The authors thank the European Organization for Research and Treatment of Cancer for permission to use the data from EORTC studies 26053/22054 (CATNON) and 26091 (TAVAREC) for this research. Publisher Copyright: © 2021, The Author(s).

PY - 2021/6

Y1 - 2021/6

N2 - Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

AB - Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

KW - Astrocytoma

KW - Gene expression

KW - Genome-wide DNA methylation

KW - IDH1

KW - IDH2

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UR - http://www.scopus.com/inward/citedby.url?scp=85103099135&partnerID=8YFLogxK

U2 - 10.1007/s00401-021-02291-6

DO - 10.1007/s00401-021-02291-6

M3 - Article

C2 - 33740099

AN - SCOPUS:85103099135

VL - 141

SP - 945

EP - 957

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 6

ER -

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

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