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

Authors
 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 
Citation
 Nature, Vol.560 : 243-247, 2018 
Journal Title
 Nature 
ISSN
 0028-0836 
Issue Date
2018
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.
Full Text
http://dx.doi.org/10.1038/s41586-018-0389-3
DOI
10.1038/s41586-018-0389-3
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
강석구(Kang, Seok Gu) ORCID logo https://orcid.org/0000-0001-5676-2037
김세훈(Kim, Se Hoon) ORCID logo https://orcid.org/0000-0001-7516-7372
김의현(Kim, Eui Hyun) ORCID logo https://orcid.org/0000-0002-2523-7122
윤선진(Yoon, Seon Jin) ORCID logo https://orcid.org/0000-0002-3255-5081
장종희(Chang, Jong Hee)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/163262
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