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      MYB-QKI rearrangements in Angiocentric Glioma drive tumorigenicity through a tripartite mechanism

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 1 , 9 , 1 , 3 , 4 , 4 , 5 , 1 , 3 , 1 , 1 , 3 , 1 , 3 , 4 , 5 , 5 , 10 , 11 , 12 , 6 , 7 , 6 , 7 , 6 , 7 , 5 , 6 , 7 , 6 , 7 , 6 , 7 , 5 , 5 , 1 , 3 , 4 , 13 , 14 , 14 , 1 , 15 , 4 , 5 , 2 , 3 , 3 , 16 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 26 , 27 , 27 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 32 , 34 , 35 , 32 , 36 , 1 , 10 , 11 , 12 , 1 , 3 , 5 , 37 , 38 , 39 , 40 , 13 , 9 , 41 , 2 , 42 , 43 , 44 , 45 , 46 , 6 , 7 , 45 , 2 , 4 , 1 , 3 , 5 , 10 , 11 , 12 , 1 , 3 , 5 , 37 , 6 , 7 , 45 , 47
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          Abstract

          Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs including 19 Angiocentric Gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in Angiocentric Gliomas. In vitro and in vivo functional studies show MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI. This represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

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          Most cited references45

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          Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.

          Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.
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            Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.

            Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.
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              • Record: found
              • Abstract: found
              • Article: not found

              Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system

              Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                20 January 2016
                01 February 2016
                24 February 2016
                01 August 2016
                : 48
                : 3
                : 273-282
                Affiliations
                [1 ]Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
                [2 ]Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts, USA
                [3 ]The Broad Institute, Cambridge, Massachusetts, USA
                [4 ]Harvard Medical School, Boston, Massachusetts, USA
                [5 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
                [6 ]Division of Neurosurgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
                [7 ]Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
                [8 ]Cell & Molecular Biology Graduate Group, Gene Therapy and Vaccines Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
                [9 ]Department de Cancerologie de l’Enfant et de l’Adolescent et Unité Mixte de Recherche du Centre National de la Recherche Scientifique 8203 "Vectorologie et Nouvelles Therapeutiques du Cancer", Gustave Roussy, Universite Paris XI Sud, Villejuif, France
                [10 ]Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
                [11 ]Department of Pathology, Boston Children’s Hospital, Boston, Massachusetts, USA
                [12 ]Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
                [13 ]Broad Technology Labs, The Broad Institute, Cambridge, Massachusetts, USA
                [14 ]Laboratoire de Neuropathologie, Hopital Sainte-Anne, Universite Paris V Descartes, Paris, France
                [15 ]Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA
                [16 ]Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
                [17 ]Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
                [18 ]Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
                [19 ]Pathology Unit, Anna Meyer Children's University Hospital, Florence, Italy
                [20 ]Neurosurgery Unit-Neuroscience Department, Anna Meyer Pediatric Hospital, University of Florence, Florence, Italy
                [21 ]Division of Pediatric Hematology-Oncology, UT Southwestern Medical School, Dallas, Texas, USA
                [22 ]Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
                [23 ]Departement de Neurochirurgie, Hopital Necker-Enfants Malades, Universite Paris V Descartes, Paris, France
                [24 ]Department of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada
                [25 ]Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
                [26 ]Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
                [27 ]Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [28 ]Brain Tumor Institute, Children’s National Medical Center, Washington, District of Columbia, USA
                [29 ]Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children’s National Medical Center, Washington, District of Columbia, USA
                [30 ]Department of Pathology, Children’s National Medical Center, Washington, District of Columbia, USA
                [31 ]Department of Neurology, University of California San Francisco School of Medicine, San Francisco, California, USA
                [32 ]Department of Neurological Surgery, University of California San Francisco School of Medicine, San Francisco, California, USA
                [33 ]Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, California, USA
                [34 ]Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco School of Medicine, San Francisco, California, USA
                [35 ]Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, USA
                [36 ]Department of Pathology, UCSF, San Francisco, CA, USA
                [37 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
                [38 ]Division of Experimental Medicine, Montreal Children’s Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada
                [39 ]Department of Human Genetics, McGill University, Montreal, Quebec, Canada
                [40 ]Department of Pediatrics, McGill University, Montreal, Quebec, Canada
                [41 ]Brigham and Women’s Hospital Department of Pathology, Center for Advanced Molecular Diagnostics, Division of Cytogenetics, Boston, Massachusetts, USA
                [42 ]Department of Neurosurgery, Boston Children’s Hospital, Boston, Massacusetts, USA
                [43 ]Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts, USA
                [44 ]Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
                [45 ]Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
                [46 ]Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
                [47 ]Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
                Author notes
                Co-corresponding authors:, Keith L. Ligon ( keith_ligon@ 123456dfci.harvard.edu ), Adam Resnick ( RESNICK@ 123456email.chop.edu ), and Rameen Beroukhim ( Rameen_Beroukhim@ 123456dfci.harvard.edu )

                Equal contributions statement Pratiti Bandopadhayay, Lori Ramkissoon, Payal Jain and Guillaume Bergthold contributed equally as co-first authors.

                Keith L. Ligon, Adam Resnick and Rameen Beroukhim contributed equally as co-corresponding authors.

                Article
                NIHMS750014
                10.1038/ng.3500
                4767685
                26829751
                7b3b640d-ddac-43f2-97b1-d461460c898c

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