BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors

• Published in: Nature medicine Vol. 24; no. 11; pp. 1662 - 1668
• Main Authors: Koh, Hyun Yong, Kim, Se Hoon, Jang, Jaeson, Kim, Hyungguk, Han, Sungwook, Lim, Jae Seok, Son, Geurim, Choi, Junjeong, Park, Byung Ouk, Heo, Won Do, Han, Jinju, Lee, Hyunjoo Jenny, Lee, Daeyoup, Kang, Hoon-Chul, Shong, Minho, Paik, Se-Bum, Kim, Dong Seok, Lee, Jeong Ho
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2018; Nature Publishing Group
• Subjects: 692/617/375/178; 692/617/375/1922; Biomedical and Life Sciences; Biomedicine; Brain; Brain cancer; Brain tumors; Cancer Research; Cell proliferation; Cells (biology); Complications and side effects; Development and progression; Drug approval; Epilepsy; Gene mutation; Gene sequencing; Gene silencing; Genetic aspects; Genetic research; Health aspects; Infectious Diseases; Ion channels; Letter; Metabolic Diseases; Molecular Medicine; Mutation; Neural stem cells; Neurons; Neurosciences; Neurotransmitter receptors; Pediatric epilepsy; Pediatric tumors; Pediatrics; Progenitor cells; Receptors; Rest; Ribonucleic acid; Risk factors; RNA; RNA sequencing; Seizures; Seizures (Medicine); Tumors
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0172-x

Pediatric brain tumors are highly associated with epileptic seizures 1 . 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 epilepsy 2 . To do so, we developed a mouse model harboring the BRAF V600E somatic mutation during early brain development to reflect the most frequent mutation, as well as the origin and timing thereof. Therein, the BRAF V600E 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 BRAF V600E -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 BRAF V600E 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. In pediatric brain tumors that are accompanied by epileptic seizures, the BRAF somatic mutation V600E contributes to intrinsic epileptic properties in neurons, which can be suppressed by vemurafenib in mice.