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

Joo Ho Lee, Jeong Eun Lee, Jee Ye Kahng, SeHoon 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 journalLetter

45 Citations (Scopus)

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 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

Fingerprint

Lateral Ventricles
Glioblastoma
Mutation
Neural Stem Cells
Isocitrate Dehydrogenase
Brain
Brain Neoplasms
Astrocytes
Neoplasms
High-Throughput Nucleotide Sequencing
Microdissection
Medical Genetics
Glioma
Disease Progression
Molecular Biology
Lasers
Genome
Survival

All Science Journal Classification (ASJC) codes

  • General

Cite this

Lee, J. H., Lee, J. E., Kahng, J. Y., Kim, S., Park, J. S., Yoon, S. J., ... Lee, J. H. (2018). Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature, 560(7717), 243-247. https://doi.org/10.1038/s41586-018-0389-3
Lee, Joo Ho ; Lee, Jeong Eun ; Kahng, Jee Ye ; Kim, SeHoon ; 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. / Human glioblastoma arises from subventricular zone cells with low-level driver mutations. In: Nature. 2018 ; Vol. 560, No. 7717. pp. 243-247.
@article{3e0a38c57a95405192ec71b6f648be9e,
title = "Human glioblastoma arises from subventricular zone cells with low-level driver mutations",
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 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.",
author = "Lee, {Joo Ho} and Lee, {Jeong Eun} and Kahng, {Jee Ye} and SeHoon Kim and Park, {Jun Sung} and Yoon, {Seon Jin} and Um, {Ji Yong} and Kim, {Woo Kyeong} and Lee, {June Koo} and Junseong Park and Kim, {Eui Hyun} and Lee, {Ji Hyun} and Lee, {Joon Hyuk} and Chung, {Won Suk} and Ju, {Young Seok} and Park, {Sung Hong} and Chang, {Jong Hee} and Seok-Gu Kang and Lee, {Jeong Ho}",
year = "2018",
month = "8",
day = "9",
doi = "10.1038/s41586-018-0389-3",
language = "English",
volume = "560",
pages = "243--247",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7717",

}

Lee, JH, Lee, JE, Kahng, JY, Kim, S, Park, JS, Yoon, SJ, Um, JY, Kim, WK, Lee, JK, Park, J, Kim, EH, Lee, JH, Lee, JH, Chung, WS, Ju, YS, Park, SH, Chang, JH, Kang, S-G & Lee, JH 2018, 'Human glioblastoma arises from subventricular zone cells with low-level driver mutations', Nature, vol. 560, no. 7717, pp. 243-247. https://doi.org/10.1038/s41586-018-0389-3

Human glioblastoma arises from subventricular zone cells with low-level driver mutations. / Lee, Joo Ho; Lee, Jeong Eun; Kahng, Jee Ye; Kim, SeHoon; 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.

In: Nature, Vol. 560, No. 7717, 09.08.2018, p. 243-247.

Research output: Contribution to journalLetter

TY - JOUR

T1 - Human glioblastoma arises from subventricular zone cells with low-level driver mutations

AU - Lee, Joo Ho

AU - Lee, Jeong Eun

AU - Kahng, Jee Ye

AU - Kim, SeHoon

AU - Park, Jun Sung

AU - Yoon, Seon Jin

AU - Um, Ji Yong

AU - Kim, Woo Kyeong

AU - Lee, June Koo

AU - Park, Junseong

AU - Kim, Eui Hyun

AU - Lee, Ji Hyun

AU - Lee, Joon Hyuk

AU - Chung, Won Suk

AU - Ju, Young Seok

AU - Park, Sung Hong

AU - Chang, Jong Hee

AU - Kang, Seok-Gu

AU - Lee, Jeong Ho

PY - 2018/8/9

Y1 - 2018/8/9

N2 - 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 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.

AB - 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 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.

UR - http://www.scopus.com/inward/record.url?scp=85051249592&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051249592&partnerID=8YFLogxK

U2 - 10.1038/s41586-018-0389-3

DO - 10.1038/s41586-018-0389-3

M3 - Letter

VL - 560

SP - 243

EP - 247

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7717

ER -