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

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dc.contributor.authorLee, Joo Hoko
dc.contributor.authorLee, Jeong Eunko
dc.contributor.authorKahng, Jee Yeko
dc.contributor.authorKim, Se Hoonko
dc.contributor.authorPark, Jun Sungko
dc.contributor.authorYoon, Seon Jinko
dc.contributor.authorUm, Ji-Yongko
dc.contributor.authorKim, Woo Kyeongko
dc.contributor.authorLee, June Kooko
dc.contributor.authorPark, Junseongko
dc.contributor.authorKim, Eui Hyunko
dc.contributor.authorLee, Ji-Hyunko
dc.contributor.authorLee, Joon Hyukko
dc.contributor.authorChung, Won-Sukko
dc.contributor.authorJu, Young Seokko
dc.contributor.authorPark, Sung-Hongko
dc.contributor.authorChang, Jong Heeko
dc.contributor.authorKang, Seok-Guko
dc.contributor.authorLee, Jeong Hoko
dc.date.accessioned2018-09-18T05:51:38Z-
dc.date.available2018-09-18T05:51:38Z-
dc.date.created2018-08-27-
dc.date.created2018-08-27-
dc.date.issued2018-08-
dc.identifier.citationNATURE, v.560, no.7717, pp.243 - +-
dc.identifier.issn0028-0836-
dc.identifier.urihttp://hdl.handle.net/10203/245405-
dc.description.abstractGlioblastoma (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.-
dc.languageEnglish-
dc.publisherNATURE PUBLISHING GROUP-
dc.subjectTERT PROMOTER MUTATIONS-
dc.subjectGROSS-TOTAL RESECTION-
dc.subjectNEURAL STEM-CELLS-
dc.subjectSOMATIC MUTATIONS-
dc.subjectCANCER-
dc.subjectBRAIN-
dc.subjectGLIOMA-
dc.subjectSURVIVAL-
dc.subjectREVEALS-
dc.subjectVARIANT-
dc.titleHuman glioblastoma arises from subventricular zone cells with low-level driver mutations-
dc.typeArticle-
dc.identifier.wosid000441115200050-
dc.identifier.scopusid2-s2.0-85051249592-
dc.type.rimsART-
dc.citation.volume560-
dc.citation.issue7717-
dc.citation.beginningpage243-
dc.citation.endingpage+-
dc.citation.publicationnameNATURE-
dc.identifier.doi10.1038/s41586-018-0389-3-
dc.contributor.localauthorChung, Won-Suk-
dc.contributor.localauthorJu, Young Seok-
dc.contributor.localauthorPark, Sung-Hong-
dc.contributor.localauthorLee, Jeong Ho-
dc.contributor.nonIdAuthorLee, Jeong Eun-
dc.contributor.nonIdAuthorKahng, Jee Ye-
dc.contributor.nonIdAuthorKim, Se Hoon-
dc.contributor.nonIdAuthorYoon, Seon Jin-
dc.contributor.nonIdAuthorUm, Ji-Yong-
dc.contributor.nonIdAuthorKim, Woo Kyeong-
dc.contributor.nonIdAuthorPark, Junseong-
dc.contributor.nonIdAuthorKim, Eui Hyun-
dc.contributor.nonIdAuthorLee, Ji-Hyun-
dc.contributor.nonIdAuthorChang, Jong Hee-
dc.contributor.nonIdAuthorKang, Seok-Gu-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordPlusTERT PROMOTER MUTATIONS-
dc.subject.keywordPlusGROSS-TOTAL RESECTION-
dc.subject.keywordPlusNEURAL STEM-CELLS-
dc.subject.keywordPlusSOMATIC MUTATIONS-
dc.subject.keywordPlusCANCER-
dc.subject.keywordPlusBRAIN-
dc.subject.keywordPlusGLIOMA-
dc.subject.keywordPlusSURVIVAL-
dc.subject.keywordPlusREVEALS-
dc.subject.keywordPlusVARIANT-
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