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Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas.

ABSTRACT: Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished on the basis of the IDH mutation and 1p/19q co-deletion. Here we present an integrated analysis of the transcriptome, genome and methylome of 156 OT. Not only does our multi-omics classification match the current classification but also reveals three subgroups within 1p/19q co-deleted tumours, associated with specific expression patterns of nervous system cell types: oligodendrocyte, oligodendrocyte precursor cell (OPC) and neuronal lineage. We confirm the validity of these three subgroups using public datasets. Importantly, the OPC-like group is associated with more aggressive clinical and molecular patterns, including MYC activation. We show that the MYC activation occurs through various alterations, including MYC genomic gain, MAX genomic loss, MYC hypomethylation and microRNA-34b/c down-regulation. In the lower grade glioma TCGA dataset, the OPC-like group is associated with a poorer outcome independently of histological grade. Our study reveals previously unrecognized heterogeneity among 1p/19q co-deleted tumours.

SUBMITTER: Kamoun A

PROVIDER: S-EPMC4838899 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:High-grade gliomas are malignant neuroepithelial tumors. The current WHO classification for adult-type diffuse gliomas is based on IDH1/2 mutational and 1p/19q-codeletion status, which can be refined by emerging genomics, transcriptomics, and methylomics approaches. Nevertheless, therapy has been dominated by radiochemotherapy for about 15 years and progressed little in efficacy or precision through advanced molecular patient stratification. Glioma proteome alterations remain undercharacterized despite their promise for a better stratification and, in particular, the identification of therapeutic targets. Here, we used mass spectrometry (MS) to characterize 42 formalin-fixed, paraffin-embedded (FFPE) samples from IDH-wildtype (IDHwt), IDH-mutant (IDHmut) gliomas with and without 1p/19q-codeletion, and non-neoplastic brain tissue controls. Based on more than 5500 quantified proteins and 5000 phospho-sites, gliomas separated according to IDH1/2 mutational status and reflected loss of proteins encoded on 1p/19q in IDHmut, gains on chromosome 7 and losses on chromosome 10 in IDHwt. Unexpectedly, the 1p/19q-codeletion resulted in minor proteome changes. Instead, two proteomic subtypes of IDHmut gliomas showed major perturbations of mitochondrial DNA-encoded proteins, aerobic/anaerobic energy metabolism, RNA metabolism, chromatin dynamics, the extracellular matrix as well as tumor suppressor and oncoproteins. Reanalysis of three glioma proteomics studies independently validate the observed hallmarks and associate these proteomic subtypes with the well-established proneural and classic/mesenchymal IDHwt glioma subtypes. These results suggest an alternative stratification of IDHmut gliomas as part of common phenotypic subtypes independent of the IDH status, with broad therapeutic implications for patients with IDHmut gliomas in the future. Altogether, our study provides a rich protein and phospho-site resource restratifying glioma subtypes and supporting future mechanism of action and target discovery investigations.

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Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas.

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