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Nat Commun. 2016 Apr 6;7:11185. doi: 10.1038/ncomms11185.

Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma.

Author information

1
Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.
2
McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
3
Research Center for Genetic Medicine, Children's National Health System, Washington, District Of Columbia 20010, USA.
4
Institute for Biomedical Sciences, George Washington University School of Medicine and Health Sciences, Washington, District Of Columbia 20052, USA.
5
Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, Québec, Canada H4A 3J1.
6
Division of Pathology, Children's National Health System, Washington, District Of Columbia 20010, USA.
7
Center for Cancer and Blood Disorders, Children's National Health System, Washington, District Of Columbia 20010, USA.
8
The Department of Neurological Surgery, George Washington University School of Medicine and Health Sciences, Washington, District Of Columbia 20052, USA.
9
Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusett 02115, USA.
10
Department of Pathology, CHU Ste-Justine, Université de Montréal, Montreal, Québec, Canada H3T 1C5.
11
UQ Child Health Research Centre, The University of Queensland, Brisbane, Queensland 4101, Australia.
12
University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland 4102, Australia.
13
Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland 4101, Australia.
14
National Cancer Institute, National Institute of Health, Bethesda, Maryland 20892, USA.
15
Department of Pathology, Montreal Neurological Hospital, McGill University, Montreal, Québec, Canada H3A 2B4.
16
Brain Tumour Institute, Center for Neuroscience and Behavioral Medicine, Children's National Health System, Washington, District Of Columbia, 20010, USA.
17
Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, District Of Columbia 20052, USA.

Abstract

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.

PMID:
27048880
PMCID:
PMC4823825
DOI:
10.1038/ncomms11185
[Indexed for MEDLINE]
Free PMC Article

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