机构：[1]Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China神经外科首都医科大学宣武医院介入放射科[2]State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China[3]Department of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, Canada[4]Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada[5]Department of Public Health, Nanjing Medical University, Nanjing, China
The genetic basis of many brain and spinal arteriovenous malformations is unclear. Hong et al. reveal a causative role for somatic tumour-related mutations in KRAS/BRAF in the majority of patients tested. This homogeneity supports therapeutic targeting of the RAS/RAF/MAPK pathway without the need for tissue genetic diagnosis.Brain and spinal arteriovenous malformations are congenital lesions causing intracranial haemorrhage or permanent disability especially in young people. We investigated whether the vast majority or all brain and spinal arteriovenous malformations are associated with detectable tumour-related somatic mutations. In a cohort of 31 patients (21 with brain and 10 with spinal arteriovenous malformations), tissue and paired blood samples were analysed with ultradeep next generation sequencing of a panel of 422 common tumour genes to identify the somatic mutations. We used droplet digital polymerase chain reaction to confirm the panel sequenced mutations and identify the additional low variant frequency mutations. The association of mutation variant frequencies and clinical features were analysed. The average sequencing depth was 1077 298. High prevalence (87.1%) of KRAS/BRAF somatic mutations was found in brain and spinal arteriovenous malformations with no other replicated tumour-related mutations. The prevalence of KRAS/BRAF mutation was 81.0% (17 of 21) in brain and 100% (10 of 10) in spinal arteriovenous malformations. We detected activating BRAF mutations and two novel mutations in KRAS (p.G12A and p.S65_A66insDS) in CNS arteriovenous malformations for the first time. The mutation variant frequencies were negatively correlated with nidus volumes of brain (P = 0.038) and spinal (P = 0.028) arteriovenous malformations but not ages. Our findings support a causative role of somatic tumour-related mutations of KRAS/BRAF in the overwhelming majority of brain and spinal arteriovenous malformations. This pathway homogeneity and high prevalence implies the development of targeted therapies with RAS/RAF pathway inhibitors without the necessity of tissue genetic diagnosis.
基金：
This study was supported by National Key R&D Program
of China with grants 2016YFC1300800 to H.Z. and
2017YFC0909400 to Y.W.; National Natural Science
Foundation of China with grants 81671202 to H.Z.,
81701151 to T.H. and 81770424 to Y.W.; Beijing
Municipal Science and Technology Commission with
grant D161100003816001 to H.Z., D161100003816006
to T.H.; Beijing Municipal Administration of Hospitals’
Ascent Plan with grant DFL20180801 to H.Z. and
Chinese Academy of Medical Sciences with Innovation
Fund for Medical Sciences CAMS2017-I2M-1-008 to Y.W.
第一作者机构：[1]Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
共同第一作者：
通讯作者：
通讯机构：[*1]Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College 167 Beilishi Rd, Beijing, 100037, China
推荐引用方式(GB/T 7714)：
Hong Tao,Yan Yupeng,Li Jingwei,et al.High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations[J].BRAIN.2019,142(1):23-34.doi:10.1093/brain/awy307.
APA：
Hong, Tao,Yan, Yupeng,Li, Jingwei,Radovanovic, Ivan,Ma, Xiangyuan...&Wang, Yibo.(2019).High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations.BRAIN,142,(1)
MLA：
Hong, Tao,et al."High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations".BRAIN 142..1(2019):23-34
医学