Enrichment of oligodendrocyte precursor phenotypes in subsets of low-grade glioneuronal tumors

Abstract Current histological classification of low-grade glioneuronal tumors (LGNT) does not adequately represent their underlying biology. The neural lineage(s) and differentiation stage(s) involved, and the cell state(s) affected by the recurrent genomic alterations are unclear. Here, we describe dysregulated oligodendrocyte lineage developmental programs in three LGNT subtypes. Ten dysembryoplastic neuroepithelial tumors (DNET), four myxoid glioneuronal tumors (MGNT), and five rosette-forming glioneuronal tumors (RGNT) were collected. Besides a comprehensive characterization of clinical features, known diagnostic markers, and genomic alterations, we used comprehensive immunohistochemical stainings to characterize activation of rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathway, involvement of neuronal component, resemblance to glial lineages and differentiation blockage along the stages of oligodendrocyte lineage. The findings were further complemented by gene set enrichment analysis with transcriptome data of DNETs from the literature. DNETs, MGNTs, and RGNTs occur at different ages, with symptoms closely related to tumor location. DNETs and MGNTs contain oligodendrocyte-like cells and neuronal component. RGNTs contained regions of rosette-forming neurocytic and astrocytic features. Scatted neurons, identified by neuronal nuclei antigen (NeuN) and microtubule-associated protein-2 (MAP-2) staining, were consistently observed in all DNETs and MGNTs examined, but only in one RGNT. Pervasive neurofilament (NF)-positive axons were observed only in DNET and MGNT samples. Alterations in B-Raf proto-oncogene, serine/threonine kinase (BRAF), fibroblast growth factor receptor 1 (FGFR1), FGFR3, and platelet derived growth factor receptor alpha (PDGFRA) occurred in a mutually exclusive manner, coinciding with strong staining of phospho-p44/42 MAPK (p-Erk1/2) and low apoptotic signal. All DNETs, MGNTs, and the neurocytic regions of RGNTs showed strong expression of neuron-glia antigen 2 (NG2), PDGFRA (markers of oligodendrocyte precursor cells (OPC)) and neurite outgrowth inhibitor-A (Nogo-A) (a marker of developing oligodendrocytes), but lacked the expression of oligodendrocyte markers ectonucleotide pyrophosphatase/phosphodiesterase family member 6 (ENPP6) and myelin basic protein (MBP). Notably, transcriptomes of DNETs were enriched in OPC signature, but not in signatures of neural stem cells, myelinating oligodendrocytes, and astrocytes. DNET, MGNT, and RGNT resemble OPCs, their enrichment of OPC phenotypes is closely associated with the recurrent mutations in RAS/MAPK pathway.