1. Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.
- Author
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Mondal G, Lee JC, Ravindranathan A, Villanueva-Meyer JE, Tran QT, Allen SJ, Barreto J, Gupta R, Doo P, Van Ziffle J, Onodera C, Devine P, Grenert JP, Samuel D, Li R, Metrock LK, Jin LW, Antony R, Alashari M, Cheshier S, Whipple NS, Bruggers C, Raffel C, Gupta N, Kline CN, Reddy A, Banerjee A, Hall MD, Mehta MP, Khatib Z, Maher OM, Brathwaite C, Pekmezci M, Phillips JJ, Bollen AW, Tihan T, Lucas JT Jr, Broniscer A, Berger MS, Perry A, Orr BA, and Solomon DA
- Subjects
- Adolescent, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Child, Child, Preschool, Epigenesis, Genetic genetics, ErbB Receptors genetics, Female, Glioma drug therapy, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Protein Kinase Inhibitors pharmacology, Carcinoma, Non-Small-Cell Lung genetics, Glioma genetics, Mutation genetics
- 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.
- Published
- 2020
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