Original Paper

Acta Neuropathologica

, Volume 127, Issue 6, pp 881-895

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

  • Amanda M. SaratsisAffiliated withDivision of Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of ChicagoCenter for Genetic Medicine Research, Children’s National Medical Center
  • , Madhuri KambhampatiAffiliated withCenter for Genetic Medicine Research, Children’s National Medical Center
  • , Kendall SnyderAffiliated withCenter for Genetic Medicine Research, Children’s National Medical Center
  • , Sridevi YadavilliAffiliated withCenter for Genetic Medicine Research, Children’s National Medical Center
  • , Joseph M. DevaneyAffiliated withCenter for Genetic Medicine Research, Children’s National Medical CenterDepartment of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences
  • , Brennan HarmonAffiliated withCenter for Genetic Medicine Research, Children’s National Medical Center
  • , Jordan HallAffiliated withCenter for Genetic Medicine Research, Children’s National Medical Center
  • , Eric H. RaabeAffiliated withDivision of Neuro-Pathology, Johns Hopkins University School of MedicineDivision of Pediatric Oncology, Johns Hopkins University School of Medicine
  • , Ping AnAffiliated withDivision of Neuro-Pathology, Johns Hopkins University School of MedicineNeurobiology Department, College of Basic Medical Sciences, China Medical University
    • , Melanie WeingartAffiliated withDivision of Neuro-Pathology, Johns Hopkins University School of Medicine
    • , Brian R. RoodAffiliated withDivision of Oncology, Center for Cancer and Immunology Research, Children’s National Medical Center
    • , Suresh N. MaggeAffiliated withDivision of Neurosurgery, Children’s National Medical Center
    • , Tobey J. MacDonaldAffiliated withDepartment of Pediatrics, Emory University School of Medicine
    • , Roger J. PackerAffiliated withDivision of Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of ChicagoDivision of Neurology, Center for Neuroscience Research, Children’s National Medical CenterBrain Tumor Institute, Center for Neuroscience and Behavioral Medicine, Children’s National Medical Center
    • , Javad NazarianAffiliated withCenter for Genetic Medicine Research, Children’s National Medical CenterDepartment of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences Email author 

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Abstract

Diffuse intrinsic pontine glioma (DIPG) is a highly morbid form of pediatric brainstem glioma. Here, we present the first comprehensive protein, mRNA, and methylation profiles of fresh-frozen DIPG specimens (n = 14), normal brain tissue (n = 10), and other pediatric brain tumors (n = 17). Protein profiling identified 2,305 unique proteins indicating distinct DIPG protein expression patterns compared to other pediatric brain tumors. Western blot and immunohistochemistry validated upregulation of Clusterin (CLU), Elongation Factor 2 (EF2), and Talin-1 (TLN1) in DIPGs studied. Comparisons to mRNA expression profiles generated from tumor and adjacent normal brain tissue indicated two DIPG subgroups, characterized by upregulation of Myc (N-Myc) or Hedgehog (Hh) signaling. We validated upregulation of PTCH, a membrane receptor in the Hh signaling pathway, in a subgroup of DIPG specimens. DNA methylation analysis indicated global hypomethylation of DIPG compared to adjacent normal tissue specimens, with differential methylation of 24 genes involved in Hh and Myc pathways, correlating with protein and mRNA expression patterns. Sequencing analysis showed c.83A>T mutations in the H3F3A or HIST1H3B gene in 77 % of our DIPG cohort. Supervised analysis revealed a unique methylation pattern in mutated specimens compared to the wild-type DIPG samples. This study presents the first comprehensive multidimensional protein, mRNA, and methylation profiling of pediatric brain tumor specimens, detecting the presence of two subgroups within our DIPG cohort. This multidimensional analysis of DIPG provides increased analytical power to more fully explore molecular signatures of DIPGs, with implications for evaluating potential molecular subtypes and biomarker discovery for assessing response to therapy.

Keywords

Diffuse intrinsic pontine glioma (DIPG) Brainstem glioma Proteomics Histone H3 Myc oncogene Hedgehog