BMB Reports 2018; 51(10): 481-483  https://doi.org/10.5483/BMBRep.2018.51.10.233
The origin-of-cell harboring cancer-driving mutations in human glioblastoma
Joo Ho Lee1, Jeong Ho Lee2,*
1Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, 2Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea
Correspondence to: E-mail: jhlee4246@kaist.ac.kr
Received: September 17, 2018; Published online: October 31, 2018.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Glioblastoma (GBM) is the most common and aggressive form of human adult brain malignancy. The identification of the cell of origin harboring cancer-driver mutations is the fundamental issue for understanding the nature of GBM and developing the effective therapeutic target. It has been a long-term hypothesis that neural stem cells in the subventricular zone (SVZ) might be the origin-of-cells in human glioblastoma since they are known to have life-long proliferative activity and acquire somatic mutations. However, the cell of origin for GBM remains controversial due to lack of direct evidence thereof in human GBM. Our recent study using various sequencing techniques in triple matched samples such as tumor-free SVZ, tumor, and normal tissues from human patients identified the clonal relationship of driver mutations between GBM and tumor-free SVZ harboring neural stem cells (NSCs). Tumor-free SVZ tissue away from the tumor contained low-level GBM driver mutations (as low as 1% allelic frequency) that were found in the dominant clones in its matching tumors. Moreover, via single-cell sequencing and microdissection, it was discovered that astrocyte-like NSCs accumulating driver mutations evolved into GBM with clonal expansion. Furthermore, mutagenesis of cancer-driving genes of NSCs in mice leads to migration of mutant cells from SVZ to distant brain and development of high-grade glioma through the aberrant growth of oligodendrocyte precursor lineage. Altogether, the present study provides the first direct evidence that NSCs in human SVZ is the cell of origin that develops the driver mutations of GBM.
Keywords: Glioblastoma, Neural stem cell, Somatic mutation, Subventricular zone


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Funding Information
  • Ministry of Health and Welfare(Ministry of Health, Welfare and Family Affairs)
      10.13039/501100003625
      H15C3143, H16C0415
  • National Research Foundation of Korea(NRF)
      10.13039/501100003725
     
  • Ministry of Education(Ministry of Education of the Republic of Korea)
      10.13039/501100002701
      NRF-2014H1A2A1021321

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