Human glioblastoma arises from subventricular zone cells with low-level driver mutations

Joo Ho Lee, Jeong Eun Lee, Jee Ye Kahng, Se Hoon Kim, Jun Sung Park, Seon Jin Yoon, Ji Yong Um, Woo Kyeong Kim, June Koo Lee, Junseong Park, Eui Hyun Kim, Ji Hyun Lee, Joon Hyuk Lee, Won Suk Chung, Young Seok Ju, Sung Hong Park, Jong Hee Chang, Seok Gu Kang, Jeong Ho Lee

Research output: Contribution to journalArticlepeer-review

195 Citations (Scopus)

Abstract

Glioblastoma (GBM) is a devastating and incurable brain tumour, with a median overall survival of fifteen months1,2. Identifying the cell of origin that harbours mutations that drive GBM could provide a fundamental basis for understanding disease progression and developing new treatments. Given that the accumulation of somatic mutations has been implicated in gliomagenesis, studies have suggested that neural stem cells (NSCs), with their self-renewal and proliferative capacities, in the subventricular zone (SVZ) of the adult human brain may be the cells from which GBM originates3–5. However, there is a lack of direct genetic evidence from human patients with GBM4,6–10. Here we describe direct molecular genetic evidence from patient brain tissue and genome-edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that contains the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of (i) normal SVZ tissue away from the tumour mass, (ii) tumour tissue, and (iii) normal cortical tissue (or blood), from 28 patients with isocitrate dehydrogenase (IDH) wild-type GBM or other types of brain tumour. We found that normal SVZ tissue away from the tumour in 56.3% of patients with wild-type IDH GBM contained low-level GBM driver mutations (down to approximately 1% of the mutational burden) that were observed at high levels in their matching tumours. Moreover, by single-cell sequencing and laser microdissection analysis of patient brain tissue and genome editing of a mouse model, we found that astrocyte-like NSCs that carry driver mutations migrate from the SVZ and lead to the development of high-grade malignant gliomas in distant brain regions. Together, our results show that NSCs in human SVZ tissue are the cells of origin that contain the driver mutations of GBM.

Original languageEnglish
Pages (from-to)243-247
Number of pages5
JournalNature
Volume560
Issue number7717
DOIs
Publication statusPublished - 2018 Aug 9

Bibliographical note

Funding Information:
Acknowledgements We thank J. K. Kim for discussing single-cell sequencing. This work was supported by grants from Suh Kyungbae Foundation and IBS-R002-D1 to J.H.L. (last author), the Korean Health Technology R&D Project, Ministry of Health & Welfare, South Korea (H15C3143 and H16C0415 to J.H.L. (last author), HI14C1324 and HI17C2586 to S.G.K.), the Global PhD Fellowship Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Republic of Korea (NRF-2014H1A2A1021321 to J.H.L. (first author)), the Basic Science Research Program through the NRF of Korea (NRF-2016R1D1A1A09916521 to S.G.K.) funded by the Ministry of Education, the NRF of Korea grant (NRF-2017M2A2A7A01071036 to S.G.K.) funded by the Korean Ministry of Science, ICT and Future Planning, the Basic Science Research Program through the NRF of Korea (NRF-2017R1A2B2006526 to S.P.) funded by the Ministry of Science, ICT and Future Planning, and Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI16C2387 to Y.S.J.) funded by the Ministry of Health and Welfare. Non-cancer brain tissues were provided by the Netherlands Brain Bank (project number Lee-835) to J.H.L. (last author).

Publisher Copyright:
© 2018, Springer Nature Limited.

All Science Journal Classification (ASJC) codes

  • General

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