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Nat Genet. 2014 May;46(5):451-6. doi: 10.1038/ng.2936. Epub 2014 Apr 6.

Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.

Author information

1
1] Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. [2] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. [4].
2
1] Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, North Carolina, USA. [2].
3
1] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
4
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
5
Génome Québec Innovation Centre, McGill University, Montreal, Quebec, Canada.
6
Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
7
Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, New York, USA.
8
Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
9
Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, North Carolina, USA.
10
1] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
11
Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
12
Department of Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.
13
Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
14
Department of Pediatrics-Hematology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
15
Division of Pediatric Hematology/Oncology and Neuropathology, New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA.
16
Department of Pediatrics, Children's Hospital Colorado, Denver, Colorado, USA.
17
Department of Pathology, Arnold Palmer Hospital for Children, Orlando, Florida, USA.
18
Clark H. Smith Brain Tumour Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
19
Department of Pediatric Neurology and Neuro-Oncology, BC Children's Hospital, Vancouver, British Columbia, Canada.
20
Division of Hematology/Oncology, McMaster Children's Hospital, Hamilton, Ontario, Canada.
21
Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
22
Department of Hematology/Oncology, Children's Hospital London Health Sciences Centre, London, Ontario, Canada.
23
Monash Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, Australia.
24
Department of Neurological Surgery, Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
25
1] Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. [2] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

PMID:
24705254
PMCID:
PMC3997489
DOI:
10.1038/ng.2936
[Indexed for MEDLINE]
Free PMC Article
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