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:
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.
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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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 -