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

Abstract

Identifying the cell of origin that harbors an initial driver mutation is key to understanding tumor evolution and for the development of new treatments. For isocitrate dehydrogenase (IDH)-mutant gliomas, the most common malignant primary brain tumor in young adults, the cell of origin is currently poorly understood. We conducted deep sequencing on 142 tissues from 70 individuals comprising tumors, peritumoral cortex or subventricular zones, and blood. Low-level <i>IDH</i> mutations were found in the peritumoral cortex in 37.9% (11 of 29) of patients. Integrating cell-type-specific mutation analysis, the direction of clonal evolution, spatial transcriptomics from patient brains, and a cancer mouse model arising from mutant oligodendrocyte progenitor cell, we determined that glial progenitor cells harboring an initial <i>IDH</i> mutation were responsible for the development of IDH-mutant gliomas.