Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations
AuthorsTesileanu, C. M. S.
Vallentgoed, W. R.
Clement, P. M.
Brandes, A. A.
Baurain, J. F.
Chinot, O. L.
McBain, Catherine A
Enting, R. H.
de Vos, F.
Mulholland, P. J.
Taphoorn, M. J. B.
de Heer, I.
de Wit, M.
Vogelbaum, M. A.
Nowak, A. K.
Mason, W. P.
Kros, J. M.
Jenkins, R. B.
Dubbink, H. J.
van den Bent, M.
French, P. J.
AffiliationDepartment of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute Rotterdam, PO Box 2040, 3000 CA, Rotterdam
MetadataShow full item record
AbstractSomatic 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.
CitationTesileanu 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.
- Loss of H3K27 trimethylation is frequent in IDH1-R132H but not in non-canonical IDH1/2 mutated and 1p/19q codeleted oligodendroglioma: a Japanese cohort study.
- Authors: Habiba U, Sugino H, Yordanova R, Ise K, Tanei ZI, Ishida Y, Tanikawa S, Terasaka S, Sato KI, Kamoshima Y, Katoh M, Nagane M, Shibahara J, Tsuda M, Tanaka S
- Issue date: 2021 May 21
- Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation.
- Authors: Ferreira MSV, Sørensen MD, Pusch S, Beier D, Bouillon AS, Kristensen BW, Brümmendorf TH, Beier CP, Beier F
- Issue date: 2020 Mar
- IDH1/2 gene hotspot mutations in central nervous system tumours: analysis of 922 Chinese patients.
- Authors: Chen N, Yu T, Gong J, Nie L, Chen X, Zhang M, Xu M, Tan J, Su Z, Zhong J, Zhou Q
- Issue date: 2016 Dec
- Loss of BCAT1 Expression is a Sensitive Marker for IDH-Mutant Diffuse Glioma.
- Authors: Chen YY, Ho HL, Lin SC, Hsu CY, Ho DM
- Issue date: 2019 Sep 1
- Characteristics of IDH-mutant gliomas with non-canonical IDH mutation.
- Authors: Poetsch L, Bronnimann C, Loiseau H, Frénel JS, Siegfried A, Seizeur R, Gauchotte G, Cappellen D, Carpentier C, Figarella-Branger D, Eimer S, Meyronet D, Ducray F, POLA network.
- Issue date: 2021 Jan