Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms11185
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Funding
- Genome Canada
- Genome Quebec
- Institute for Cancer Research of the Canadian Institutes for Health Research (CIHR) McGill University
- Montreal Children's Hospital Foundation
- NIH National Center for Advancing Translational Sciences [UL1TR000075, KL2TR000076]
- Smashing Walnuts Foundation (Middleburg, VA)
- Zickler Family Foundation (Chevy Chase, MD)
- Goldwin Foundation (St Lincoln, NE)
- Piedmont Community Foundation (Middleburg, VA)
- Musella Foundation (Hewlett, NY)
- Mathew Larson Foundation (Franklin Lake, NJ)
- Brain Tumour Foundation for Children Atlanta, GA)
- Chair de Recherche from le Fond de Recherche en Sante au Quebec
- CIHR
- T.D trust/Montreal Children's Hospital Foundation
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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.
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