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Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.

ABSTRACT: The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3^id ) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3^id . Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3^id overexpressing neuronal intermediate progenitor (NIP) genes was identified. This NIP overexpression pattern in O3^id is associated with: (i) morphological and immunohistochemical similarities with embryonic subventricular zone, (ii) proliferating tumor cell subpopulation with NIP features including expression of INSM1 and no expression of SOX9, (iii) mutations in critical genes involved in NIP biology and, (iv) increased tumor necrosis. Interestingly, NIP tumor cell subpopulation increases in O3^id recurrence compared with paired newly diagnosed tumors. Our results, validated in an independent cohort, emphasize intertumor and intratumor heterogeneity in O3^id and identified a tumor cell subpopulation exhibiting NIP characteristics that is potentially critical in oncogenesis of O3^id . A better understanding of spatial and temporal intratumor cell heterogeneity in O3^id will open new therapeutic avenues overcoming resistance to current antitumor treatments.

SUBMITTER: Bielle F

PROVIDER: S-EPMC8029323 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.

Bielle Franck F Ducray François F Mokhtari Karima K Dehais Caroline C Adle-Biassette Homa H Carpentier Catherine C Chanut Anaïs A Polivka Marc M Poggioli Sylvie S Rosenberg Shai S Giry Marine M Marie Yannick Y Duyckaerts Charles C Sanson Marc M Figarella-Branger Dominique D Idbaih Ahmed A

Brain pathology (Zurich, Switzerland) 20161028 5

The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3<sup>id</sup> ) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3<sup>id</sup> . Based on pathological, transcriptomic and immunophenotypic studies, a novel sub ...[more]

PMID: 27543943

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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.

Dataset Information

Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.

Publications

Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.

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