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Nature. 2017 Jul 19;547(7663):311-317. doi: 10.1038/nature22973.

The whole-genome landscape of medulloblastoma subtypes.

Author information

1
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
3
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
6
Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario.
7
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
Biotech Research &Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory, Rigshospitalet, Denmark.
9
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
10
German Cancer Consortium (DKTK), Heidelberg, Germany.
11
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
12
Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Berlin, Germany.
13
Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
14
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
15
Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany.
16
Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
17
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
18
Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
19
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
20
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
21
Department of Oncogenomics, Amsterdam Medical Center, Amsterdam, Netherlands.
22
Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia.
23
Department of Pediatrics, Papé Family Pediatric Research Institute, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
24
Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
25
Department of Neurosurgery, University Clinic, Heidelberg University, Heidelberg Hospital, Germany.
26
Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany.
27
Department of Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.
28
Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
29
Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Barcelona, Spain.
30
Department of Pathology, Duke University, Durham, North County, USA.
31
Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
32
Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Japan.
33
Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
34
Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
35
Division of Neurosurgery, Hospital for Sick Children, Toronto, Ontario, Canada.

Abstract

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

PMID:
28726821
PMCID:
PMC5905700
DOI:
10.1038/nature22973
[Indexed for MEDLINE]
Free PMC Article

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