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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism
  • Autopsy
  • Brain Mapping
  • Brain Stem / metabolism
  • Brain Stem / pathology
  • Brain Stem Neoplasms / genetics*
  • Brain Stem Neoplasms / metabolism
  • Brain Stem Neoplasms / pathology
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cerebrum / metabolism
  • Cerebrum / pathology
  • Child
  • Class Ia Phosphatidylinositol 3-Kinase
  • Clonal Evolution
  • Gene Expression Regulation, Neoplastic*
  • Glioma / genetics*
  • Glioma / metabolism
  • Glioma / pathology
  • Histones / genetics*
  • Histones / metabolism
  • Humans
  • Mutation*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Protein Phosphatase 2C
  • Signal Transduction
  • Stereotaxic Techniques
  • Time Factors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Histones
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • PIK3R1 protein, human
  • Class Ia Phosphatidylinositol 3-Kinase
  • ACVR1 protein, human
  • Activin Receptors, Type I
  • PPM1D protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C