IDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation

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 128 tissues from 62 patients (29 IDH-mutant gliomas and 33 IDH-negative controls) comprising tumors, normal cortex or normal subventricular zone (SVZ), and blood. Surprisingly, low-level IDH mutation was found in the normal cortex away from the tumor in 38.5% (10 of 26) of IDH-mutant glioma patients, whereas no IDH mutation was detected in the normal SVZ. Furthermore, by analyzing cell-type–specific mutations, the direction of clonal evolution, the single-cell transcriptome from patient brains and novel mouse model of IDH-mutant glioma arising from mutation-carrying 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. Competing Interest Statement J.H.L. is a co-founder and chief scientific officer of Sovargen Inc. Y.S.J. is a co-founder and chief executive officer of Inocras Inc. The remaining authors declare no competing interests.