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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We thank the staff of the UCSF Clinical Cancer Genomics Laboratory for assistance with genetic profiling. B.A. Orr is supported by the National Cancer Institute, National Institutes of Health (P30 CA021765) and the American Lebanese Syrian Associated Charities (ALSAC). D.A. Solomon is supported by the NIH Director’s Early Independence Award from the Office of the Director, National Institutes of Health (DP5 OD021403) and a Developmental Research Program Award from the UCSF Brain Tumor SPORE grant from the National Cancer Institute, National Institutes of Health (P50 CA097257).
Conflict of interest
S.J. Allen is a current employee of Illumina, Inc. No potential conflicts of interest were disclosed by any of the other authors.
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Mondal, G., Lee, J.C., Ravindranathan, A. et al. Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition. Acta Neuropathol 139, 1071–1088 (2020). https://doi.org/10.1007/s00401-020-02155-5
- Bithalamic glioma
- Diffuse midline glioma
- Histone H3
- Pediatric cancer
- Molecular neuropathology
- Tyrosine kinase inhibitor