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. 2024 May 6;6(3):fcae156.
doi: 10.1093/braincomms/fcae156. eCollection 2024.

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

Zejun Duan  1 , Jing Feng  1 , Yuguang Guan  2 , Shouwei Li  2 , Bin Wu  2 , Yang Shao  3   4 , Zhong Ma  1 , Zejuan Hu  1 , Lei Xiang  1 , Mingwang Zhu  5 , Xiaolong Fan  6   7 , Xueling Qi  1
Affiliations

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

Zejun Duan et al. Brain Commun. .

Abstract

Current histological classification of low-grade glioneuronal tumours 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 programmes in three low-grade glioneuronal tumour subtypes. Ten dysembryoplastic neuroepithelial tumours, four myxoid glioneuronal tumours and five rosette-forming glioneuronal tumours 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 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 dysembryoplastic neuroepithelial tumours from the literature. Dysembryoplastic neuroepithelial tumours, myxoid glioneuronal tumours and rosette-forming glioneuronal tumours occur at different ages, with symptoms closely related to tumour location. Dysembryoplastic neuroepithelial tumours and myxoid glioneuronal tumours contain oligodendrocyte-like cells and neuronal component. Rosette-forming glioneuronal tumours contained regions of rosette-forming neurocytic and astrocytic features. Scattered neurons, identified by neuronal nuclei antigen and microtubule-associated protein-2 staining, were consistently observed in all dysembryoplastic neuroepithelial tumours and myxoid glioneuronal tumours examined, but only in one rosette-forming glioneuronal tumour. Pervasive neurofilament-positive axons were observed only in dysembryoplastic neuroepithelial tumour and myxoid glioneuronal tumour samples. Alterations in B-Raf proto-oncogene, serine/threonine kinase, fibroblast growth factor receptor 1, fibroblast growth factor receptor 3 and platelet-derived growth factor receptor alpha occurred in a mutually exclusive manner, coinciding with strong staining of phospho-p44/42 mitogen-activated protein kinase and low apoptotic signal. All dysembryoplastic neuroepithelial tumours, myxoid glioneuronal tumours and the neurocytic regions of rosette-forming glioneuronal tumours showed strong expression of neuron-glia antigen 2, platelet-derived growth factor receptor alpha (markers of oligodendrocyte precursor cells) and neurite outgrowth inhibitor-A (a marker of developing oligodendrocytes), but lacked the expression of oligodendrocyte markers ectonucleotide pyrophosphatase/phosphodiesterase family member 6 and myelin basic protein. Notably, transcriptomes of dysembryoplastic neuroepithelial tumours were enriched in oligodendrocyte precursor cell signature, but not in signatures of neural stem cells, myelinating oligodendrocytes and astrocytes. Dysembryoplastic neuroepithelial tumour, myxoid glioneuronal tumour and rosette-forming glioneuronal tumour resemble oligodendrocyte precursor cells, and their enrichment of oligodendrocyte precursor cell phenotypes is closely associated with the recurrent mutations in rat sarcoma/mitogen-activated protein kinase pathway.

Keywords: RAS/MAPK pathway; differentiation stage; low-grade glioneuronal tumour; neural lineage; oligodendrocyte precursor cells.

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Conflict of interest statement

The authors report no competing interests.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Preoperative images of representative cases in this study. (A) Preoperative MRI image of DNET-5 showing a hyperintensity on T2-weighted images of thickening cortex within temporal lobe without surrounding tumoural oedema. (B) Preoperative MRI image of MGNT-2 showing a well-circumscribed, FLAIR isointensity or hyperintense mass lesion in the interventricular foramen. (C) Preoperative MRI image of RGNT-3 showing a lump mass located in the sellar region with abnormal enhancement. (D) Multiple circular signals in the bilateral basal ganglia and medial temporal lobes were observed in RGNT-4. Arrows indicate the lesion.
Figure 2
Figure 2
Morphological features of DNET, MGNT and RGNT samples examined. HE stainings of representative DNET case (A) and MGNT case (B). Tumours contained OLCs with small monotonous round to oval nuclei. Proliferative cells were rare. Scattered neurons were found in the mucinous matrix (black arrows) (×400). (C) Tumour tissue was infiltrating into the white matter in the form of push invasion in MGNT-2 (black arrow) (×200). Typical RGNT (RGNT-2) contained a rosette-forming neurocytic component (black arrow indicating neurocytic rosettes and perivascular pseudorosettes) (D) and an astrocytic component (E) (×200). (F) MGNT-1 contained regions with scattered and clustered neurons, which is similar to normal white matter (×200).
Figure 3
Figure 3
Mutually exclusive genomic alterations leading to elevated RAS/MAPK and low apoptotic activities in DNET, MGNT and RGNT tumours. (A) Recurrent genomic alterations in the RAS/MAPK pathway. In 19 LGNTs analysed, 17 LGNTs harboured 1 or 2 alterations along the RAS/MAPK pathway. Except for mutations in NF1, alterations in BRAF and receptor tyrosine kinases occurred in a mutually exclusive manner across the samples. AKT1, v-akt murine thymoma viral oncogene homologue 1. (B) Representative immunohistochemical images of p-Erk1/2 staining in DNET, MGNT and RGNT samples. Strong p-Erk1/2 staining was observed in all DNET and MGNT samples examined and in the neurocytic components of RGNTs (×400, scale bar: 50 μm). (C) Anti-cleaved caspase-3 staining in DNET, MGNT and RGNT samples (×400, scale bar: 50 μm).
Figure 4
Figure 4
Pervasive axon components in DNET and MGNT samples examined. Representative IHC images of NeuN, MAP-2, NF and PSD95 stainings in DNET, MGNT and RGNT samples are shown (×400). In DNET samples, NeuN- and MAP-2-stained neuronal cell bodies were scattered in the tumour mass, while NF- and PSD95-stained axons were widely dispersed. In MGNT samples, NeuN and MAP-2 staining showed the rare neurons, while NF- and PSD95-stained axons were less widely dispersed. However, NeuN, MAP-2, NF and PSD95 stainings were negative in almost all RGNT samples examined. Scale bar: 50 μm.
Figure 5
Figure 5
Concordant expression of pan-oligodendrocyte lineage markers and OPC markers and dominating cell population expressing OPC markers in DNET, MGNT and RGNT samples analysed. (A) IHC images of representative DNET (DNET-2), MGNT (MGNT-1) and the neurocytic (RGNT-N) regions of RGNT (RGNT-1) cases are shown. Strong positive stainings of OLIG2, SOX10, NG2, PDGFRA and Nogo-A in DNET, MGNT and RGNT-N tumour cells were observed. Images were taken at ×400. Scale bar: 50 μm. (B) Quantification revealed significant increase in cells expressing PDGFRA and NG2. (Left) PDGFRA: DNET, N = 10, ***: paired t-test, t = −16.184, P = 5.821e−08; MGNT, N = 3, *: paired t-test, t = −7.0336, P = 0.01962; RGNT, N = 4, **: paired t-test, t = −6.8238, P = 0.006439; (Right) NG2: DNET, N = 10, ***: paired t-test, t = −10.94, P = 1.686e−06; MGNT, N = 3, ***: paired t-test, t = −69.412, P = 0.0002075; RGNT, N = 4, ***: paired t-test, t = −17.691, P = 0.0003938. Each data point represents the average number of positive cells/mm2 in an individual sample. Detailed data was included in Supplementary Table 3.
Figure 6
Figure 6
Enrichment of OPC signature in DNET tumours. (A) Single-sample GSEA with signature genes of NES, OPC, NFO, MO and Astro in DNET. Each data point represents enrichment score of an individual sample. The middle thick line represents the median enrichment score; the lower and upper limits represent standard deviation of the enrichment score. Adjusted P-values for ANOVA test with post hoc Bonferroni correction are indicated as *P < 0.05 and ****P < 0.0001. (B) Preranked GSEA with the OPC or NSC signature in DNET transcriptomes versus DA transcriptomes. NES, normalized enrichment score; FDR, false discovery rate.
Figure 7
Figure 7
A schematic model depicting the interplay between the neural cell states and driving genomic alterations in the LGNTs examined. LGNTs are currently diagnosed based on histological features; biologically distinct entities among LGNTs have been thus far unclear. Characteristics of the neural cell states involved may provide a consensus for LGNT diagnosis that converges the features of glial lineage/differentiation stage involved and the driving signalling pathway and thereby defines biologically distinct entities in LGNTs.
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