Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain

作者：Sergey I. Nikolaev, Sandra Vetiska, Ximena Bonilla, Émilie Boudreau, Suvi Jauhiainen, Behnam Rezai Jahromi, Nadiya Khyzha, Peter V. DiStefano, Santeri Suutarinen, Tim‐Rasmus Kiehl, Vítor Mendes Pereira, Alexander M. Herman, Timo Krings, Hugo Andrade-Barazarte, Takyee Tung, Taufik A. Valiante, Gelareh Mohammed Zadeh, Mike Tymianski, Tuomas H. Rauramaa, Seppo Ylä‐Herttuala, Joshua D. Wythe, Stylianos E. Antonarakis, Juhana Frösén, Jason E. Fish, Ivan Radovanovic · 发表于：New England Journal of Medicine · 年份：2018 · DOI：10.1056/nejmoa1709449 · 被引用次数：480 · 研究领域：Vascular Malformations Diagnosis and Treatment、Cerebrovascular and genetic disorders、Vascular Anomalies and Treatments

BACKGROUND: Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. METHODS: We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. RESULTS: ) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling. CONCLUSIONS: We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of...