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Science, 8 Jan 2026 Vol 391, Issue 6781 | DOI: 10.1126/science.adt0559 IDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation

Jung Won Park¹, Jiehoon Kwak¹, Keon-Woo Kim¹, Saehoon Jung¹, Chang Hyun Nam¹, Hyun Jung Kim^1,2, Sang Mee Lee³, Chanho Choi¹, Yongjin Ahn¹, Ji-Hyung Park^1,4, Jihwan Yoo⁵, Jin-Kyoung Shim⁶, Hye Joung Cho⁶, Eui-Hyun Kim⁶, Chungyeul Kim⁷, Sangjeong Ahn^8,9,10, Stefan Pusch^11,12, Andreas von Deimling^11,12, Jong Hee Chang^6,13, Se Hoon Kim¹⁴, Hoon Kim¹⁵, Young Seok Ju^1,16, Seok-Gu Kang^6,13,17*, Jeong Ho Lee^1,3*

¹Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
²Department of Anatomy, College of Medicine,Korea University, Seoul, Republic of Korea.
³Sovargen Inc., Daejeon, Republic of Korea.
⁴Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁵Department of Neurosurgery, Brain Tumor Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁶Department of Neurosurgery, BrainTumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁷Department of Pathology, Korea University College of Medicine, Seoul, Republic of Korea.
⁸Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
⁹Artificial Intelligence Center, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
¹⁰Department of Medical Informatics, Korea University College of Medicine, Seoul, Republic of Korea.
¹¹Department for Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹²Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), GermanCancer Consortium (DKTK), and Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany.
¹³Department of Neurosurgery, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
¹⁴Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
¹⁵Department of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
¹⁶Inocras Inc., San Diego, CA, USA.
¹⁷Brain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.

*Corresponding authors: S.-G.K.; J.H.L.

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 IDH 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 IDH mutation were responsible for the development of IDH-mutant gliomas.

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