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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.


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.

SUBMITTER: Tesileanu CMS 

PROVIDER: S-EPMC8113211 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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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.

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

Acta neuropathologica 20210319 6


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<sup>R132H</sup> mutations. Patients harbouring IDH1<sup>R132H</sup> mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations  ...[more]

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