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      Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

      research-article
      1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 4 , 1 , 2 , 5 , 6 , 5 , 7 , 5 , 7 , 8 , 9 , 9 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 24 , 24 , 24 , 24 , 25 , 26 , 27 , 27 , 28 , 29 , 30 , 30 , 31 , 31 , 32 , 3 , 33 , 33 , 33 , 34 , 35 , 5 , 36 , 37 , 38 , 43 , 37 , 43 , 39 , 40 , 41 , 42 , 8 , 5 , 6 , 7 , 1 , 2 , 44 ,
      Cancer Cell
      Cell Press
      genome, exome, methylation, histone, glioblastoma, DIPG

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          Summary

          We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

          Graphical Abstract

          Highlights

          • Pediatric HGG and DIPG comprise a diverse set of clinical and biological subgroups

          • Somatic coding mutations per tumor range from none to among the highest seen in human cancer

          • Histone mutations co-segregate with distinct alterations and downstream pathways

          • H3/IDH1 WT tumors may resemble low-grade lesions and have targetable alterations

          Abstract

          Mackay et al. perform an integrated analysis of >1,000 cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma. They identify co-segregating mutations in histone-mutant subgroups and show that histone wild-type subgroups are molecularly more similar to lower-grade tumors.

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          Most cited references34

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          Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion

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            The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression.

            Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is ∼1 yr. Here we show that the levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis.
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              Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7.

              The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain. However, the turnover of c-Myc is largely dependent on phosphorylation of threonine-58 and serine-62 in MB1, residues that are often mutated in cancer. We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c-Myc. Accumulation of c-Myc was also apparent in mouse Fbw7-/- embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively.
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                Author and article information

                Contributors
                Journal
                Cancer Cell
                Cancer Cell
                Cancer Cell
                Cell Press
                1535-6108
                1878-3686
                09 October 2017
                09 October 2017
                : 32
                : 4
                : 520-537.e5
                Affiliations
                [1 ]Division of Molecular Pathology, The Institute of Cancer Research, London, UK
                [2 ]Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
                [3 ]Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA
                [4 ]Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK
                [5 ]The Center for Data Driven Discovery in Biomedicine (D 3b), Children's Hospital of Philadelphia, Philadelphia, PA, USA
                [6 ]Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA
                [7 ]Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
                [8 ]Institute of Molecular Life Sciences, Swiss Institute of Bioinformatics, University of Zürich, Zürich, Switzerland
                [9 ]Pediatric Oncology Drug Development Team, Children and Young People's Unit, Royal Marsden Hospital, Sutton, UK
                [10 ]Department of Radiotherapy, Royal Marsden Hospital, Sutton, UK
                [11 ]Department of Cellular Pathology, St George's Hospital NHS Trust, London, UK
                [12 ]Department of Neurosurgery, St George's Hospital NHS Trust, London, UK
                [13 ]Department of Neuropathology, Kings College Hospital, London, UK
                [14 ]Department of Neurosurgery, Kings College Hospital, London, UK
                [15 ]Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
                [16 ]Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China
                [17 ]Department of Pathology, Shandong University School of Medicine, Jinan, China
                [18 ]Department of Cytogenetics and Reproductive Biology, Farhat Hached Hospital, Sousse, Tunisia
                [19 ]Department of Pathology, Morozov Children's Hospital, Moscow, Russian Federation
                [20 ]Department of Pathology, Dmitrii Rogachev Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
                [21 ]UQ Child Health Research Centre, The University of Queensland, Brisbane, Australia
                [22 ]Oncology Services Group, Children's Health Queensland Hospital and Health Service, Brisbane, Australia
                [23 ]The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia
                [24 ]Institut de Recerca Sant Joan de Deu, Barcelona, Spain
                [25 ]Division of Oncology, Pediatric Oncology and Radiotherapy, St Petersburg State Pediatric Medical University, St Petersburg, Russian Federation
                [26 ]Department of Pathology, Federal University of São Paulo, São Paulo, São Paulo, Brazil
                [27 ]Molecular Oncology Research Centre, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
                [28 ]Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal and ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
                [29 ]Pédiatrie Onco-Hématologie - Pédiatrie III, Centre Hospitalier Régional et Universitaire Hautepierre, Strasbourg, France
                [30 ]Histopathology Department, Beaumont Hospital, Dublin, Ireland
                [31 ]Department of Neurosurgery, Temple Street Children's University Hospital, Dublin, Ireland
                [32 ]Department of Paediatric Oncology, Our Lady's Children's Hospital, Dublin, Ireland
                [33 ]Département de Cancerologie de l'Enfant et de l'Adolescent, Institut Gustav Roussy, Villejuif, France
                [34 ]Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Canada
                [35 ]Department of Pediatrics, McGill University, Montreal, Canada
                [36 ]Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA
                [37 ]Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [38 ]Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
                [39 ]Department of Pediatrics, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA
                [40 ]Department of Pediatrics, Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Goettingen, Germany
                [41 ]Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Geneva, Switzerland
                [42 ]Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland
                [43 ]Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
                Author notes
                []Corresponding author chris.jones@ 123456icr.ac.uk
                [44]

                Lead Contact

                Article
                S1535-6108(17)30362-8
                10.1016/j.ccell.2017.08.017
                5637314
                28966033
                9a0ed0ba-ba17-49aa-b7ad-ad4428f0a1e3
                © 2017 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 5 May 2017
                : 14 July 2017
                : 29 August 2017
                Categories
                Article

                Oncology & Radiotherapy
                genome,exome,methylation,histone,glioblastoma,dipg
                Oncology & Radiotherapy
                genome, exome, methylation, histone, glioblastoma, dipg

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