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

Lee, Joo Ho, Lee, Jeong Eun, Kahng, Jee Ye, Kim, Se Hoon, Park, Jun Sung, Yoon, Seon Jin, Um, Ji-Yong, Kim, Woo Kyeong, Lee, June-Koo, Park, Junseong, Kim, Eui Hyun, Lee, Ji-Hyun, Lee, Joon-Hyuk, Chung, Won-Suk, Ju, Young Seok, Park, Sung-Hong, Chang, Jong Hee, Kang, Seok-Gu, Lee, Jeong Ho·2018·Nature
DOI 10.1038/s41586-018-0389-3
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Abstract

Glioblastoma (GBM) is a devastating and incurable brain tumour, with a median overall survival of fifteen months 1,2 . 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 originates 3-5 . However, there is a lack of direct genetic evidence from human patients with GBM 4,6-10 . 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 microd…

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Metadata

Authors
Lee, J. H., Lee, J. E., Kahng, J. Y., Kim, S. H., Park, J. S., Yoon, S. J., Um, J.-Y., Kim, W. K., Lee, J.-K., Park, J., Kim, E. H., Lee, J.-H., Lee, J.-H., Chung, W.-S., Ju, Y. S., Park, S.-H., Chang, J. H., Kang, S.-G., & Lee, J. H.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2018-08
Volume
560
Issue
7717
Pages
243-247
ISSN
  • 0028-0836
  • 1476-4687
DOI
10.1038/s41586-018-0389-3
Cited by
630
References
6
Language
en
Licence
www.springer.com/tdm (tdm)

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