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Nat Genet. 2016 Mar;48(3):273-82. doi: 10.1038/ng.3500. Epub 2016 Feb 1.

MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.

Author information

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
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, 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 and 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, Université 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 Laboratories, Broad Institute, Cambridge, Massachusetts, USA.
14
Laboratoire de Neuropathologie, Hopital Sainte-Anne, Université 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, 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, Anna Meyer Children's Hospital, University of Florence, Florence, Italy.
21
Division of Pediatric Hematology-Oncology, University of Texas 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, Université Paris V Descartes, Paris, France.
24
Division 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, DC, USA.
29
Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children's National Medical Center, Washington, DC, USA.
30
Department of Pathology, Children's National Medical Center, Washington, DC, 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, University of California San Francisco, San Francisco, California, 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, Massachusetts, USA.
43
Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts, USA.
44
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
45
Center for Childhood Cancer Research, 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
Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
48
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
49
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

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 that 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. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

PMID:
26829751
PMCID:
PMC4767685
DOI:
10.1038/ng.3500
[Indexed for MEDLINE]
Free PMC Article

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