Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin

Purpose: Mutation in isocitrate dehydrogenase 1 (IDH1) at R132 (IDH1 ^R132MUT) is frequent in low-grade diffuse gliomas and, within glioblastoma (GBM), has been proposed as a marker for GBMs that arise by transformation from lower-grade gliomas, regardless of clinical history. To determine how GBMs arising with IDH1 ^R132MUT differ from other GBMs, we undertook a comprehensive comparison of patients presenting clinically with primary GBM as a function of IDH1 ^R132mutation status. Patients and Methods: In all, 618 treatment-naive primary GBMs and 235 lower-grade diffuse gliomas were sequenced for IDH1 ^R132 and analyzed for demographic, radiographic, anatomic, histologic, genomic, epigenetic, and transcriptional characteristics. Results: Investigation revealed a constellation of features that distinguishes IDH1 ^R132MUT GBMs from other GBMs (including frontal location and lesser extent of contrast enhancement and necrosis), relates them to lower-grade IDH1 ^R132MUT gliomas, and supports the concept that IDH1 ^R132MUTgliomas arise from a neural precursor population that is spatially and temporally restricted in the brain. The observed patterns of DNA sequence, methylation, and copy number alterations support a model of ordered molecular evolution of IDH1 ^R132MUT GBM in which the appearance of mutant IDH1 protein is an initial event, followed by production of p53 mutant protein, and finally by copy number alterations of PTEN and EGFR. Conclusion: Although histologically similar, GBMs arising with and without IDH1 ^R132MUT appear to represent distinct disease entities that arise from separate cell types of origin as the result of largely nonoverlapping sets of molecular events. Optimal clinical management should account for the distinction between these GBM disease subtypes.