Segregation of non-p.R132H mutations in IDH1 in distinct molecular subtypes of glioma

Lonneke A M Gravendeel, Nanne K Kloosterhof, Linda B C Bralten, Ronald van Marion, Hendrikus Jan Dubbink, Winand Dinjens, Fonnet E Bleeker, Casper C Hoogenraad, Erna Michiels, Johan M Kros, Martin van den Bent, Peter A E Sillevis Smitt, Pim J French
Human Mutation 2010, 31 (3): E1186-99
Mutations in the gene encoding the isocitrate dehydrogenase 1 gene (IDH1) occur at a high frequency (up to 80%) in many different subtypes of glioma. In this study, we have screened for IDH1 mutations in a cohort of 496 gliomas. IDH1 mutations were most frequently observed in low grade gliomas with c.395G>A (p.R132H) representing >90% of all IDH1 mutations. Interestingly, non-p.R132H mutations segregate in distinct histological and molecular subtypes of glioma. Histologically, they occur sporadically in classic oligodendrogliomas and at significantly higher frequency in other grade II and III gliomas. Genetically, non-p.R132H mutations occur in tumors with TP53 mutation, are virtually absent in tumors with loss of heterozygosity on 1p and 19q and accumulate in distinct (gene-expression profiling based) intrinsic molecular subtypes. The IDH1 mutation type does not affect patient survival. Our results were validated on an independent sample cohort, indicating that the IDH1 mutation spectrum may aid glioma subtype classification. Functional differences between p.R132H and non-p.R132H mutated IDH1 may explain the segregation in distinct glioma subtypes.

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