Zhong Liu1, Pulin Che2, Juan J Mercado3, James R Hackney3,4, Gregory K Friedman4, Cheng Zhang5, Zhiying You6, Xinyang Zhao1, Qiang Ding7, Kitai Kim8,9, Hu Li5, Xiaoguang Liu10, James M Markert4,11, Burt Nabors2, G Yancey Gillespie11, Rui Zhao12,13, Xiaosi Han14,15. 1. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. 2. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. 3. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. 4. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. 5. Department of Molecular Pharmacology & Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55904, USA. 6. Department of Medicine, University of Colorado Denver-Anschutz Medical Campus, Denver, CO, 80045, USA. 7. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. 8. Cancer Biology and Genetics Program, The Center for Cell Engineering, The Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute for Cancer Research, New York, NY, USA. 9. Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, 10065, USA. 10. Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. 11. Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. 12. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. ruizhao@uab.edu. 13. University of Alabama at Birmingham, Shelby 714, 1825 University Blvd., Birmingham, AL, 35294, USA. ruizhao@uab.edu. 14. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. xhan@uab.edu. 15. University of Alabama at Birmingham, 1020 Faculty Office Tower, 510 20th Street South, Birmingham, AL, 35294, USA. xhan@uab.edu.
Abstract
INTRODUCTION: IDH1 mutation has been identified as an early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis. METHODS: We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH). RESULTS: We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPSC clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells. CONCLUSIONS: These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.
INTRODUCTION: IDH1 mutation has been identified as an early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis. METHODS: We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH). RESULTS: We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPSC clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells. CONCLUSIONS: These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.
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