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Lind KT, Chatwin HV, DeSisto J, et al. Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation. J Neuropathol Exp Neurol. 2021;80(12):1099-1107doi: 10.1093/jnen/nlab110.
Lind, K. T., Chatwin, H. V., DeSisto, J., Coleman, P., Sanford, B., Donson, A. M., Davies, K. D., Willard, N., Ewing, C. A., Knox, A. J., Mulcahy Levy, J. M., Gilani, A., & Green, A. L. (2021). Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation. Journal of neuropathology and experimental neurology, 80(12), 1099-1107. https://doi.org/10.1093/jnen/nlab110
Lind, Katherine T, et al. "Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation." Journal of neuropathology and experimental neurology vol. 80,12 (2021): 1099-1107. doi: https://doi.org/10.1093/jnen/nlab110
Lind KT, Chatwin HV, DeSisto J, Coleman P, Sanford B, Donson AM, Davies KD, Willard N, Ewing CA, Knox AJ, Mulcahy Levy JM, Gilani A, Green AL. Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation. J Neuropathol Exp Neurol. 2021 Dec 29;80(12):1099-1107. doi: 10.1093/jnen/nlab110. PMID: 34850053.
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J Neuropathol Exp Neurol. 2021 Dec 29;80(12):1099-1107. doi: 10.1093/jnen/nlab110.

Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation.

Journal of neuropathology and experimental neurology

Katherine T Lind, Hannah V Chatwin, John DeSisto, Philip Coleman, Bridget Sanford, Andrew M Donson, Kurtis D Davies, Nicholas Willard, Calvin A Ewing, Aaron J Knox, Jean M Mulcahy Levy, Ahmed Gilani, Adam L Green

Affiliations

  1. From the Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.
  2. Department of Pediatrics, University of Colorado School of Medicine, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA.
  3. Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA.

PMID: 34850053 DOI: 10.1093/jnen/nlab110

Abstract

Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors.

© 2021 American Association of Neuropathologists, Inc. All rights reserved.

Keywords: MAPK pathway; Pediatric low-grade glioma; RAF fusions

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