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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)945-957
Number of pages13
JournalActa Neuropathologica
Volume141
Issue number6
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Acknowledgements:
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).

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