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Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain

OPEN The New England journal of medicine | 4 Jan 2018

SI Nikolaev, S Vetiska, X Bonilla, E Boudreau, S Jauhiainen, B Rezai Jahromi, N Khyzha, PV DiStefano, S Suutarinen, TR Kiehl, V Mendes Pereira, AM Herman, T Krings, H Andrade-Barazarte, T Tung, T Valiante, G Zadeh, M Tymianski, T Rauramaa, S Ylä-Herttuala, JD Wythe, SE Antonarakis, J Frösen, JE Fish and I Radovanovic
Abstract
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 We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) 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 the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).
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Concepts
Evolution, Organism, Gene expression, Signal transduction, Genetics, Blood, DNA, Gene
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