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

• 成果类型: Article
• 署名作者: Park, Jung Won; Kwak, Jiehoon; Kim, Keon-Woo; Jung, Saehoon; Nam, Chang Hyun; Kim, Hyun Jung; Lee, Sang Mee; Choi, Chanho; Ahn, Yongjin; Park, Ji-Hyung; Yoo, Jihwan; Shim, Jin-Kyoung; Cho, Hye Joung; Kim, Eui-Hyun; Kim, Chungyeul; Ahn, Sangjeong; Pusch, Stefan; von Deimling, Andreas; Chang, Jong Hee; Kim, Se Hoon; Kim, Hoon; Ju, Young Seok; Kang, Seok-Gu; Lee, Jeong Ho
• 署名单位: Korea Advanced Institute of Science & Technology (KAIST); Korea University; Korea University Medicine (KU Medicine); Yonsei University; Severance Hospital; Yonsei University Health System; Yonsei University; Severance Hospital; Yonsei University Health System; Yonsei University; Severance Hospital; Yonsei University Health System; Korea University; Korea University Medicine (KU Medicine); Korea University; Korea University Medicine (KU Medicine); Korea University; Korea University Medicine (KU Medicine); Korea University; Korea University Medicine (KU Medicine); Ruprecht Karls University Heidelberg; Helmholtz Association; German Cancer Research Center (DKFZ); Yonsei University; Yonsei University Health System; Yonsei University; Yonsei University Health System; Sungkyunkwan University (SKKU); Yonsei University; Yonsei University Health System
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adt0559
• 发表日期: 2026-01-08
• 页码: eadt0559
• 关键词: central-nervous-system; somatic mutations; neural stem; glioblastoma; expression; EVOLUTION; lineage; tumors; origin

摘要

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.