Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition

Details

• Alternative Title:
  Acta Neuropathol
• Personal Author:
  Mondal, Gourish ; Lee, Julieann C. ; Ravindranathan, Ajay ; Villanueva-Meyer, Javier E. ; Tran, Quynh T. ; Allen, Sariah J. ; Barreto, Jairo ; Gupta, Rohit ; Doo, Pamela ; Van Ziffle, Jessica ; Onodera, Courtney ; Devine, Patrick ; Grenert, James P. ; Samuel, David ; Li, Rong ; Metrock, Laura K. ; Jin, Lee-way ; Antony, Reuben ; Alashari, Mouied ; Cheshier, Samuel ; Whipple, Nicholas S. ; Bruggers, Carol ; Raffel, Corey ; Gupta, Nalin ; Kline, Cassie N. ; Reddy, Alyssa ; Banerjee, Anu ; Hall, Matthew D. ; Mehta, Minesh P. ; Khatib, Ziad ; Maher, Ossama M. ; Brathwaite, Carole ; Pekmezci, Melike ; Phillips, Joanna J. ; Bollen, Andrew W. ; Tihan, Tarik ; Lucas, John T. ; Broniscer, Alberto ; Berger, Mitchel S. ; Perry, Arie ; Orr, Brent A. ; Solomon, David A.
• Description:
  Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.
• Subjects:
  Afatinib Article Bithalamic Glioma Diffuse Midline Glioma EGFR Erlotinib Histone H3 Molecular Neuropathology Osimertinib Pediatric Cancer Trametinib Tyrosine Kinase Inhibitor

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• Source:
  Acta Neuropathol. 139(6):1071-1088
• Pubmed ID:
  32303840
• Pubmed Central ID:
  PMC7792550
• Document Type:
  Journal Article
• Funding:
  DP5 OD021403/OD/NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; DP5 OD021403/CD/ODCDC CDC HHS/United States
• Volume:
  139
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:3fc11332331c7c95ef6f077ec0f0400db49adeeb49ae3ee2b308d349aafbed20
• Download URL:
  https://stacks.cdc.gov/view/cdc/100245/cdc_100245_DS1.pdf
• File Type:
  [PDF - 1.71 MB ]