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 originates3,4,5. However, there is a lack of direct genetic evidence from human patients with GBM4,6,7,8,9,10. 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.
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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).
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Nature thanks M. Taylor and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Contributions
S.-G.K. and Jeong Ho Lee conceived the idea of the project. Joo Ho Lee, S.-G.K. and Jeong Ho Lee organised the project. Joo Ho Lee and J.E.L. performed genetic studies. Joo Ho Lee, J.-K.L. and Y.S.J. performed the analysis of the mutational signature. S.H.K. performed pathological studies in human tissues. Joo Ho Lee and J.Y.K. performed the generation and analysis of mice. Joo Ho Lee and J.Y.K. performed single-cell sequencing and laser microdissection. J.-Y.U. and S.-H.P. performed the analysis of mouse brain MRIs. J.H.C., E.H.K. and S.-G.K. performed surgeries, collected patient samples and managed tissue information with S.J.Y., Ji-Hyun Lee, Joo Ho Lee and W.K.K. J.P. performed subtype classification. J.S.P. performed genetic studies of non-cancer brain tissues. Joon-Hyuk Lee and W.-S.C. produced viral vectors. Joo Ho Lee and Jeong Ho Lee wrote the manuscript. S.-G.K. and Jeong Ho Lee led the project.
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Extended data figures and tables
Extended Data Fig. 1 Radiological and histological confirmation of sampling and tissues from patients with IDH-wild-type GBM.
a, The distance between the tumour-margin and the sampling site of SVZ tissue was measured using 3D-reconstruced MRI images. b, H&E staining of the GBM tumour shows pseudopalisading necrosis. Scale bar, 200 µm. c, H&E staining of the SVZ tissue away from the tumour shows tumour-free status with intact architecture. Scale bar, 200 µm. Radiological and histological confirmation was performed in all 30 patients. d, Pre-operation brain MRI of a patient with IDH-wild-type GBM shows the locations of sampling sites of tumour and tumour-free SVZ tissue. Multiple samplings from tumour-free SVZs were performed in two patients (GBM187 and GBM499).
Extended Data Fig. 2 VAF scatterplots of SNV and indels, and patterns of CNVs of matched tumour and tumour-free SVZ tissue.
a–c, Scatterplots from seven patients with IDH-wild-type GBM with tumour-free SVZ (a), meningioma with tumour-free SVZ (b), anaplastic oligodendroglioma, and IDH-mutant with tumour-free SVZ (c). Shared and private somatic mutations in paired SVZ and tumour (x and y axes, respectively) tissue specimens are indicated as a function of the VAF. A single point represents an individual mutation. Red dots indicate cancer-driver mutations (see Methods). d, Quantitative analysis of CNVs in EGFR in patients with IDH-wild-type GBM who harboured driver mutations thereof in tumour-free SVZ. The bar graph shows relative fold changes in EGFR copy numbers in patients GBM26, GBM187, GBM245, GBM276, GBM499 and GBM520 (relative to the matched normal control) based on qPCR. e, Genome-wide CNV plots for patients with IDH-wild-type GBM and matching tumour-free SVZs harbouring shared mutations in WES. Red and blue boxes indicate shared and tumour-private CNVs between tumour-free SVZ and tumour, respectively. f, Genome-wide CNV plots for a patient with IDH-wild-type GBM and a GBM-invaded SVZ. g, EGFR amplification was found at the cellular level through FISH of the tumour-free SVZ specimen from one patient (GBM520). FISH was performed in patients GBM26, GBM276, GBM499 and GBM520. EGFR and control probes were red and green, respectively. Scale bars, 10 µm.
Extended Data Fig. 3 VAFs of nonsynonymous somatic mutations in glioma-related genes from triple-matched samples of 23 patients with GBM and other types of brain tumour.
a, VAFs of mutations in patients with IDH-wild-type GBM and tumour-free SVZs. b, VAFs of mutations in other types of brain tumour with tumour-free SVZs. c, VAFs of mutations in patients with IDH-wild-type GBM and GBM-invaded SVZs. The lengths of the bars are proportional to the VAF (the scale bar under the last column applies to all columns).
Extended Data Fig. 4 Schematic of the experimental procedures for single-cell sequencing of tumour-private mutations and shared driver mutations in frozen tissue.
Nuclei are isolated from homogenized tissue and stained with DAPI. Flow cytometry sorts DAPI-stained nuclei as a single nucleus into each well of a 96-well plate, which is confirmed by fluorescent microscopy. Then, single-cell PCR followed by Sanger sequencing is performed.
Extended Data Fig. 5 Identification of the chronological order and clonal evaluation between SVZ and tumour.
a, b, Single-cell sequencing of tumours and tumour-free SVZ. Single-cell Sanger sequencing of tumour-private and shared driver mutations (left) and a summary of the sequencing results (right) in the tumours (a) and in the tumour-free SVZ (b) from patients who had somatic mutations shared between SVZ and tumour tissue. The numbers in the tables on the right indicate the number of sequenced clones. c, d, LCM of the three layers that make up the SVZ, followed by site-specific amplicon sequencing. c, LCM in patient GBM187 captured approximately 30 nuclei from each defined structure. Scale bar, 100 µm. d, Site-specific amplicon sequencing reveals increases in C228T mutant allele frequency from the bulk DNA to the micro-dissected astrocytic ribbon, whereas the mutation was not found in the other micro-dissected regions. Control reflects a randomly micro-dissected region from the same tumour-free SVZ specimen. e, The frequency of patients harbouring TERT promoter mutations. Numbers indicate the number (percentage) of patients. Deep-target sequencing of TERT promoter mutations (C228T and C250T) was performed. Non-cancer aged brain refers to autopsy samples of the hippocampus from non-cancer aged control brain tissues with an average age of 84 years. *P = 0.005, Fisher’s exact test. f, Mutation spectra incorporating the substitution type of mutations in the GBM-invaded SVZ. The mutation types are displayed on the horizontal axis, and the vertical axis indicates the fractions of mutations attributed to a specific mutation type. g, The number of mutations contributing to each mutation signature.
Extended Data Fig. 6 Development of high-grade glioma in genome-edited mice harbouring P53/PTEN/EGFR mutations in the SVZ.
a, The map of a single vector expressing Cas9 and Cre recombinase with the sgRNAs targeting p53/Pten. b, In vitro screen of sgRNAs targeted to p53 and Pten in the Neuro-2a cell line by transient transfection and T7E1 assay. c, Immunostaining image of markers for neural stem cells at 3 days after electroporation of the vector in P53/PTEN/EGFR-mutant mice; the image highlights the localization of tdTomato-positive cells along the SVZ co-stained with GFAP or nestin. Scale bars, 50 μm. d, A scatter dot graph showing the percentage of tdTomato-positive cells co-stained with nestin or GFAP (P53/PTEN/EGFR-mutant mouse: n = 5; mean ± s.e.m.). e, A Kaplan–Meier survival graph of mice (n = 10 mice in each group). P = 0.000063, log-rank test. f, Representative H&E-stained images reflect the classical features of high-grade glioma, such as necrosis (Fig. 3e), microvascular proliferation (M), and mitoses (arrow). Scale bars, 100 μm. g, Representative MRI images of the bulk tumours formed in the 3 mice after 16 weeks. h, Immunostaining of various high-grade glioma-related markers, including nestin, GFAP, OLIG2, S100β, MBP and Ki67, as well as the neuronal maker NeuN, in tumours (n = 4 tumours). Scale bars, 50 μm. i, The bar graph shows the percentage of sequencing reads with indels in one high-grade glioma from mutant mice, using site-specific amplicon sequencing of the CRISPR targeting region in p53 and Pten. j, Detection of EGFRviii (360 bp) in tumours from P53/PTEN/EGFR-mutant mice using quantitative PCR with reverse transcription (qRT–PCR). Actb was used as an internal control (n = 3 mice with tumours).
Extended Data Fig. 7 The formation of glioma as observed in serial sections of mouse brain.
a, Images from the P53/PTEN/EGFR-mutant mice show that the tdTomato-positive cells initially locate in the rostral SVZ, where mutations are edited. Over time, these cells migrate to distant cortical regions and proliferate to form the tumour. b, Images from wild-type mice at 16 weeks after the electroporation of the plasmid containing sgRNA for lacZ gene with the expression of Cas9/Cre as a control. In panels a and b, section points were the middle of the olfactory bulb at 0.7, −1, −2.5 and −3.5 mm apart from bregma; time intervals were 2 days, 8 weeks, 13 weeks and 16 weeks after electroporation. Scale bars, 500 μm. c, Quantification of tdTomato signal intensities corresponding to the average of cortical regions from four serial sections in the affected side. Section points were 0.7, −1, −2.5 and −3.5 mm apart from bregma. Control indicates the wild-type mouse electroporated with the plasmid containing sgRNA for the lacZ gene with the expression of Cas9/Cre. *P = 0.007, **P = 0.0002 (n = 6 for control and mutant mice at each time point), Student’s two-tailed t-test. Error bars represent mean ± s.e.m.
Extended Data Fig. 8 The normal cytoarchitecture of the SVZ and olfactory bulb containing mutation-carrying cells and viral injection targeting driver mutations in the cortex.
a, b, Immunostaining of S100β (a, ependymal cell marker), GFAP and nestin (b, stem-cell marker) in mutation-arising SVZ tissue from the mice with high-grade glioma in the distant cortical region (n = 6 mice with tumours). c, Targeted deep sequencing of TP53 and PTEN in tdTomato-positive neurons laser-captured from the olfactory bulb. The tdTomato-positive cells in the olfactory bulb were labelled with yellow dots in LCM images (targeting). Labelled cells were micro-dissected (LCM). d, Deep amplicon sequencing of CRISPR target sites showed that tdTomato-positive cells in the olfactory bulb contained P53/PTEN mutations. Scale bar, 50 μm. LCM and sequencing were repeated in 3 mice. e, Experimental scheme showing the procedure for viral injection of AAV5 containing sgRNAs for p53 and Pten genes, with the expression of Cas9 and Cre recombinase into the SVZ in LSL-EGFRviii; LSL-Cas9-GFP mice. f, g, Representative images of the injection site in the cortex at 1 week and 6 weeks after viral injection. Virus-expressing cells are GFP-positive. Scale bar, 500 μm. h, Quantification of the number of GFP-positive cells at the representative image. The section points were the sites where the highest number of GFP-positive cells are found (mice at 1 week: n = 3, mice at 4–6 weeks: n = 5). Not significant (NS), Student’s two-tailed t-test. Error bars represent mean ± s.e.m. i, Images from mouse at 6 weeks after viral injection to cortex. No signal was found in the distant brain as well as the SVZ. j, Images from mouse at 6 weeks after electroporation to the SVZ. For panels d and e, section points were 0.7, −1, −2.5 and −3.5 mm apart from bregma (mice at 1 week: n = 3, mice at 4–6 weeks: n = 5). Scale bars, 500 μm. k, Representative immunohistochemical images of GFAP-, OLIG2-, NeuN-, and GFP-positive cells at 1 week after viral injection) mice at 1 week: n = 3, mice at 4–6 weeks: n = 5). Scale bars, 100 μm.
Extended Data Fig. 9 Aberrant growth of OPC lineage in the distant region.
a, The scatter dot graph shows the percentage of cells positive for various NSC-derived cell lineage markers, such as NeuN for neurons, MBP for oligodendrocytes, GFAP for astrocytes, and PDGFRα and OLIG2 for oligodendrocyte-progenitor cells (OPCs). The average of four representative cortical regions at the caudal cortex (−3.5 mm apart from bregma) away from the mutation-arising SVZ were analysed (n = 6 for control and mutant mice). Error bars represent mean ± s.e.m. b, Representative immunostaining images of OLIG2-, PDGFRα-, GFAP- and tdTomato-positive cell regions at the caudal cortex (−3.5 mm apart from bregma). White arrows indicate tdTomato-positive cells co-stained with OLIG2 or PDGFRα. Scale bars, 50 µm. n = 6 mice c, Immunostaining of Ki67, a marker of proliferation, and cell-type markers PDGFRα, OLIG2 and GFAP in P53/PTEN/EGFR-mutant mice before the formation of a visible glioma. White arrows indicate Ki67-positive cells. Scale bars, 50 μm. n = 3 mice. d, Illustration of the progress of migration and tumour development via the aberrant growth of OPCs.
Supplementary information
Supplementary Table 1
Summary of clinical and sequencing information of patients. EGFR expression grade was evaluated by immunohistochemistry in patient samples. Gene amplification of EGFR was evaluated by fluorescence in situ hybridization. N/A, not available; WES, whole-exome sequencing; MGMT, O6-alkylguanine DNA alkyltransferase
Supplementary Table 2
A list of glioma-related genes for targeted sequencing
Supplementary Table 3
Sequencing primers for validation of mutations and the states thereof
Supplementary Table 4
Primers for quantitative PCR analysis of copy number variations in EGFR
Supplementary Table 5
Primers for single-cell sequencing
Supplementary Table 6
A list of oligonucleotides used for sgRNA construction
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Lee, J.H., Lee, J.E., Kahng, J.Y. et al. Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature 560, 243–247 (2018). https://doi.org/10.1038/s41586-018-0389-3
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DOI: https://doi.org/10.1038/s41586-018-0389-3
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