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    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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    Authors
    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, Catherine A
    Reijneveld, J.
    Enting, R. H.
    Caparrotti, F.
    Lesimple, T.
    Clenton, S.
    Gijtenbeek, A.
    Lim, E.
    de Vos, F.
    Mulholland, P. J.
    Taphoorn, M. J. B.
    de Heer, I.
    Hoogstrate, Y.
    de Wit, M.
    Boggiani, L.
    Venneker, S.
    Oosting, J.
    Bovée, J.
    Erridge, S.
    Vogelbaum, M. A.
    Nowak, A. K.
    Mason, W. P.
    Kros, J. M.
    Wesseling, P.
    Aldape, K.
    Jenkins, R. B.
    Dubbink, H. J.
    Baumert, B.
    Golfinopoulos, V.
    Gorlia, T.
    van den Bent, M.
    French, P. J.
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    Affiliation
    Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute Rotterdam, PO Box 2040, 3000 CA, Rotterdam
    Issue Date
    2021
    
    Metadata
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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.
    Citation
    Tesileanu CMS, Vallentgoed WR, Sanson M, Taal W, Clement PM, Wick W, et al. Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations. Acta Neuropathol. 2021.
    Journal
    Acta Neuropathologica
    URI
    http://hdl.handle.net/10541/623960
    DOI
    10.1007/s00401-021-02291-6
    PubMed ID
    33740099
    Additional Links
    https://dx.doi.org/10.1007/s00401-021-02291-6
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00401-021-02291-6
    Scopus Count
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