IDH-mutant glioma arises from glial progenitor cells harboring the initial driver mutation
Discovering the cell-of-origin with the initial driver mutation provides fundamental basis for understanding tumor evolution and developing new treatments. In isocitrate dehydrogenase (IDH)-mutant gliomas, the most common malignant primary brain tumors in young adult under 50, its cell-of-origin remains poorly understood. Here, we used patient brain tissues and genome edited mice to identify glial progenitor cells (GPCs) including oligodendrocyte progenitor cells (OPCs) as the cell-of-origin harboring the IDH mutation as the initial driver mutation. We conducted comprehensive deep sequencing, including droplet digital PCR and deep panel and amplicon sequencing on 128 tissues from 62 patient (29 IDH-mutant gliomas and 33 IDH-negative controls), comprising tumors, normal cortex, or normal subventricular zone (SVZ), and blood. Surprisingly, we found low-level IDH mutation in the normal cortex away from the tumor, in 38.5% (10 of 26) of IDH-mutant glioma patients, while no IDH mutation was detected in the normal SVZ. Furthermore, through the analysis of cell-type-specific mutations, the direction of clonal evolution, and the single-cell transcriptome from patient brains as well as novel mouse model of IDH-mutant glioma arising from mutation-carrying OPCs, we determined that GPCs including OPCs with the initial driver mutation are responsible for the development and evolution to 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. Overall design: To determine whether our mouse IDH-mutant glioma model accurately represents human IDH-mutant glioma at the single-cell transcriptome level, we performed single-cell RNA sequencing (scRNA-seq) in four OPC-ITAN mice (26-38 weeks old) and one control mouse (20 weeks old)