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Acta Neuropathologica
Published in: Acta Neuropathologica 6/2020

01-06-2020 | Glioblastoma | Original Paper

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

Authors: 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 Cheshier, Nicholas 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 Jr, Alberto Broniscer, Mitchel S. Berger, Arie Perry, Brent A. Orr, David A. Solomon

Published in: Acta Neuropathologica | Issue 6/2020

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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.
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Metadata
Title
Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition
Authors
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 Cheshier
Nicholas 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 Jr
Alberto Broniscer
Mitchel S. Berger
Arie Perry
Brent A. Orr
David A. Solomon
Publication date
01-06-2020
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 6/2020
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-020-02155-5

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