IDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation (Related accession no. GSE275791) - Spatial transcriptomics dataset

ABSTRACT: Discovering the cell-of-origin harboring the initial driver mutation provides a fundamental basis for understanding tumor evolution and development of new treatments. For isocitrate dehydrogenase (IDH)-mutant gliomas–the most common malignant primary brain tumors in adults under 50–the cell-of-origin remains poorly understood. Here, using patient brain tissues and genome-edited mice, we identified glial progenitor cells (GPCs), including oligodendrocyte progenitor cells (OPCs), as the glioma-originating cell type harboring the IDH mutation as the initial driver mutation. We conducted comprehensive deep sequencing, including droplet digital PCR and deep panel and amplicon sequencing to 142 tissues from 70 patients (32 IDH-mutant gliomas and 38 IDH-negative controls) comprising tumors, histologically normal peritumoral regions or subventricular zones (SVZs), and blood. Surprisingly, low-level IDH mutation was found in the normal peritumor away from the tumor in 37.9% (11 of 29) of IDH-mutant glioma patients, whereas no IDH mutation was detected in the SVZ. Integrating cell-type–specific mutations analysis, the direction of clonal evolution, spatial transcriptomics from patient brains and a novel IDH-mutant glioma mouse model arising from mutant OPCs, we determined that GPCs, including OPCs, harboring the initial driver mutation are responsible for the development and evolution of IDH-mutant gliomas. In summary, our results demonstrate that GPCs containing the IDH mutation are the cells-of-origin harboring the initial driver mutation in IDH-mutant gliomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302642 | GEO | 2026/01/13

REPOSITORIES: GEO