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

Gourish Mondal, Julieann C. Lee, Ajay Ravindranathan, Javier E. Villanueva-Meyer, Quynh T. Tran, Sariah J. Allen, Jairo Barreto, Rohit Gupta, Pamela Doo, Jessica Van Ziffle, Courtney Onodera, Patrick Devine, James P. Grenert, David Samuel, Rong Li, Laura K. Metrock, Lee way Jin, Reuben Antony, Mouied Alashari, Samuel CheshierNicholas S. Whipple, Carol Bruggers, Corey Raffel, Nalin Gupta, Cassie N. Kline, Alyssa Reddy, Anu Banerjee, Matthew D. Hall, Minesh P. Mehta, Ziad Khatib, Ossama M. Maher, Carole Brathwaite, Melike Pekmezci, Joanna J. Phillips, Andrew W. Bollen, Tarik Tihan, John T. Lucas, Alberto Broniscer, Mitchel S. Berger, Arie Perry, Brent A. Orr, David A. Solomon

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1071-1088
Number of pages18
JournalActa Neuropathologica
Volume139
Issue number6
DOIs
StatePublished - Jun 1 2020

Keywords

  • Afatinib
  • Bithalamic glioma
  • Diffuse midline glioma
  • EGFR
  • Erlotinib
  • Histone H3
  • Molecular neuropathology
  • Osimertinib
  • Pediatric cancer
  • Trametinib
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Mondal, G., Lee, J. C., Ravindranathan, A., Villanueva-Meyer, J. E., Tran, Q. T., Allen, S. J., Barreto, J., Gupta, R., Doo, P., Van Ziffle, J., Onodera, C., Devine, P., Grenert, J. P., Samuel, D., Li, R., Metrock, L. K., Jin, L. W., Antony, R., Alashari, M., ... Solomon, D. A. (2020). Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition. Acta Neuropathologica, 139(6), 1071-1088. https://doi.org/10.1007/s00401-020-02155-5