Abstract

Pediatric brain tumors are highly associated with epileptic seizures1. However, their epileptogenic mechanisms remain unclear. Here, we show that the oncogenic BRAF somatic mutation p.Val600Glu (V600E) in developing neurons underlies intrinsic epileptogenicity in ganglioglioma, one of the leading causes of intractable epilepsy2. To do so, we developed a mouse model harboring the BRAFV600E somatic mutation during early brain development to reflect the most frequent mutation, as well as the origin and timing thereof. Therein, the BRAFV600E mutation arising in progenitor cells during brain development led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to high proliferation of glial lineage cells. RNA sequencing analysis of patient brain tissues with the mutation revealed that BRAFV600E-induced epileptogenesis is mediated by RE1-silencing transcription factor (REST), which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy. Moreover, we found that seizures in mice were significantly alleviated by an FDA-approved BRAFV600E inhibitor, vemurafenib, as well as various genetic inhibitions of Rest. Accordingly, this study provides direct evidence of a BRAF somatic mutation contributing to the intrinsic epileptogenicity in pediatric brain tumors and suggests that BRAF and REST could be treatment targets for intractable epilepsy.

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Data availability

We deposited the whole-exome sequencing data reporting variants in each individual and RNA sequencing data reporting the tumor-specific transcriptome in the BioProject repository under accession numbers PRJNA481075 and PRJNA480934, respectively.

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

We thank K. S. Kim at the School of Medicine in Chungnam National University for breeding the Braflsl-V637E/+ mice, G. Mandel at Howard Hughes Medical Institute in Oregon Health and Science University for providing plasmid DNA of dnREST, and S. M. Park and W. K. Kim at the Korea Advanced Institute of Science and Technology (KAIST) for coordinating the clinical information. This work was supported by the Suh Kyungbae Foundation (to J.H.L.) and grants from the Citizens United for Research in Epilepsy (to J.H.L.) and the Korean Health Technology Research and Development (R&D) Project, Ministry of Health & Welfare, Republic of Korea (H15C3143 to J.H.L. and H16C0415 to D.S.K. and J.H.L.), KAIST (G04170025 to J.H.) and IBS-R002-D1 (to J.H.L).

Author information

Affiliations

  1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    • Hyun Yong Koh
    • , Jae Seok Lim
    • , Jinju Han
    •  & Jeong Ho Lee
  2. Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea

    • Se Hoon Kim
  3. Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea

    • Jaeson Jang
    •  & Se-Bum Paik
  4. School of Electrical Engineering, KAIST, Daejeon, Republic of Korea

    • Hyungguk Kim
    •  & Hyunjoo Jenny Lee
  5. Department of Biological Sciences, KAIST, Daejeon, Republic of Korea

    • Sungwook Han
    • , Won Do Heo
    •  & Daeyoup Lee
  6. Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon, Republic of Korea

    • Geurim Son
    • , Jinju Han
    •  & Jeong Ho Lee
  7. College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea

    • Junjeong Choi
  8. Center for Cognition and Sociality, Institute for Biological Science (IBS), Daejeon, Republic of Korea

    • Byung Ouk Park
    •  & Won Do Heo
  9. Division of Pediatric Neurology, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children’s Hospital, Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea

    • Hoon-Chul Kang
  10. Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea

    • Minho Shong
  11. Program of Brain and Cognitive Engineering, KAIST, Daejeon, Republic of Korea

    • Se-Bum Paik
  12. Department of Neurosurgery, Pediatric Epilepsy Clinics, Brain Korea 21 Project for Medical Science, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

    • Dong Seok Kim
  13. Center for Synaptic Brain Dysfunctions, IBS, Daejeon, Republic of Korea

    • Jeong Ho Lee

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Contributions

H.Y.K. organized the project and performed the genetic studies and the bioinformatics analysis with J.S.L. S.H.K. and J.C. performed the pathological studies. H.Y.K. performed the immunostaining, the biochemical in vitro work and in vivo studies with M.S. The in vivo chromatin immunoprecipitation assay was done by S.H. and H.Y.K. with D.L. Electrical signaling using multielectrodes in brain slices was recorded by H.Y.K. and analyzed by J.J. and S.-B.P. H.Y.K. performed the in vivo single-unit recording with H.K. and H.J.L. H.Y.K. performed the video EEG recording and the analysis of seizures. G.S., B.O.P., W.D.H. and J.H. prepared the viral constructs. D.S.K. performed the surgeries, collected patient samples and managed patient information and tissues samples with S.H.K. and H.-C.K. H.Y.K. and J.H.L. led the project and oversaw the manuscript preparation.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Jeong Ho Lee.

Supplementary Information

  1. Supplementary Text and Figures

    Supplementary Figures 1–9 and Supplementary Tables 1–7

  2. Reporting Summary

  3. Supplementary Video 1

    Video-EEG monitoring of wildtype Braf (left) or somatic Braf V637E mutation carrying (right) mice

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DOI

https://doi.org/10.1038/s41591-018-0172-x

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