SINGLE-NUCLEI ANALYSIS IDENTIFIES NOVEL NEOPLASTIC IDH MUTANT ASTROCYTOMA PROLIFERATIVE AND STEMNESS PHENOTYPES DRIVING POOR PATIENT OUTCOMES
Recommended Citation
Noushmehr H, Herrgott G, Garofano L, Lee I, Snyder J, Walbert T, Castro A, Iavarone A. SINGLE-NUCLEI ANALYSIS IDENTIFIES NOVEL NEOPLASTIC IDH MUTANT ASTROCYTOMA PROLIFERATIVE AND STEMNESS PHENOTYPES DRIVING POOR PATIENT OUTCOMES. Neuro Oncol 2025; 27(Supplement 5):v6.
Document Type
Conference Proceeding
Publication Date
11-11-2025
Publication Title
Neuro Oncol
Keywords
phenotype, gene expression, genetic transcription, astrocytoma, cell nucleus, chromatin, cost of illness, genes, glioma, quality control, neoplasms, poverty, transcription factor, tumor cells, rna, molecular target, therapeutic intervention, cpg island methylator phenotype, atac trial, axon guidance, patient-focused outcomes, datasets, rna-seq
Abstract
BACKGROUND: Gliomas carry a high disease burden, particularly the aggressive IDH-wildtype subtype. However, some IDH-mutant gliomas can transition from a less aggressive G-CIMP-High (GCH) state to a more malignant G-CIMP-Low (GCL) phenotype, mimicking IDH-wildtype tumors. Understanding the cellular and molecular mechanisms behind this progression is vital for developing effective therapies. HYPOTHESIS: We propose that single-nuclei resolution analysis can reveal distinct neoplastic cell subtypes driving the GCH-to-GCL transition through activation of stemness- and proliferation-related gene programs. METHODS: We analyzed 22 glioma specimens from 15 patients (including matched primary and recurrent tumors) using single-nuclei RNA- and ATAC-sequencing. After quality control and neoplastic cell identification via somatic CNVs, we applied non-negative matrix factorization (NMF) to identify cell subclusters based on gene expression patterns. We further characterized these clusters using gene set enrichment, protein-protein interaction networks, developmental trajectory analysis, and integration with external RNA-seq datasets. Chromatin accessibility was assessed via snATAC-seq to identify regulatory elements and transcription factor activity. RESULTS: We identified six major neoplastic cell subtypes: Astrocytic-Support, Pro-neural Housekeepers, Proteo-synthetic Cells, Mitotic Proliferators, Neural Guidance & Growth Cells, and Mesenchymal-mutant Cells. Each showed distinct gene expression signatures, pathway enrichments, and survival associations. Two subtypes—Mitotic Proliferators and Mesenchymal-mutant Cells—were linked to high-grade tumors and poor patient outcomes. Chromatin accessibility patterns corroborated transcriptional findings, highlighting differential TF regulation in aggressive subtypes. CONCLUSION: This study reveals two aggressive GCL-related neoplastic cell subtypes with distinct stem-like and proliferative features. These findings provide insight into glioma progression mechanisms and uncover potential molecular targets for therapeutic intervention in IDH-mutant gliomas.
Volume
27
Issue
Supplement 5
First Page
v6
