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 Vallentgoed, Marc Sanson, Walter Taal, Paul M. Clément, Wolfgang Wick, Alba A. Brandes, Jean Français Baurain, Olivier Chinot, Helen Wheeler, Sanjeev Gill, Matthew Griffin, Leland Rogers, Roberta Rudà, Michael Weller, Catherine McBain, Jaap C. Reijneveld, Roelien H. Enting, Francesca Caparrotti, Thierry Lesimple, Susan Clenton, Anja Gijtenbeek, Elizabeth Lim, Filip De Vos, Paul Mulholland, Martin 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 Mason, Johan M. Kros, Pieter Wesseling, Ken Aldape, Robert B. Jenkins, Hendrikus J. Dubbink, Brigitta G. Baumert, Vassilis Golfinopoulos, Thierry Gorlia, Martin J. van den Bent, Pim J. French
Abstract
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.