Dissecting the cell of origin in IDH-mutant glioma

Abstract

Discovering the cell of origin in brain tumors is challenging but important for fundamental basis of understanding the cancer-evolutionary process from beginning to terminal. Here, I identify the originating cell in human isocitrate dehydrogenase (IDH)-mutant glioma including astrocytoma and oligodendroglioma. I reveal that oligodendrocyte lineage cells containing oligodendrocyte progenitor cells (OPCs) and/or other glial cells harboring ultra-low-level of IDH1 alteration (> 0.115% of mutational burden) can be found in tumor-adjacent normal cortex in 62 patients with IDH-mutant glioma or other types of brain disease. As a biologic validation, OPC-specific somatic mutation mouse model exhibits hyperproliferative feature in mutant cells. Together, my results show that glial progenitor cell (GPC) as well as OPC that contain the IDH1 mutation are the cell of origin in IDH-mutant glioma.