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BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors

 Hyun Yong Koh  ;  Se Hoon Kim  ;  Jaeson Jang  ;  Hyungguk Kim  ;  Sungwook Han  ;  Jae Seok Lim  ;  Geurim Son  ;  Junjeong Choi  ;  Byung Ouk Park  ;  Won Do Heo  ;  Jinju Han  ;  Hyunjoo Jenny Lee  ;  Daeyoup Lee  ;  Hoon-Chul Kang  ;  Minho Shong  ;  Se-Bum Paik  ;  Dong Seok Kim  ;  Jeong Ho Lee 
 Nature Medicine, Vol.24(11) : 1662-1668, 2018 
Journal Title
 Nature Medicine 
Issue Date
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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1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
강훈철(Kang, Hoon Chul) ORCID logo https://orcid.org/0000-0002-3659-8847
김동석(Kim, Dong Seok)
김세훈(Kim, Se Hoon) ORCID logo https://orcid.org/0000-0001-7516-7372
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