• Mieko Oka, Mika Kushamae, Tomohiro Aoki, Tadashi Yamaguchi, Keiko Kitazato, Yu Abekura, Takakazu Kawamata, Tohru Mizutani, Susumu Miyamoto, and Yasushi Takagi.
• Department of Molecular Pharmacology, Research Institute, National Cerebral and Cardiovascular Center, Suita City, Osaka, Japan; Core Research for Evolutional Science and Technology (CREST) from Japan Agency for Medical Research and Development (AMED), National Cerebral and Cardiovascular Center, Suita City, Osaka, Japan; Department of Neurosurgery, Tokyo Women's Medical University, Shinjuku-ku, Japan.
• World Neurosurg. 2019 Jun 1; 126: e1365-e1373.

BackgroundBrain arteriovenous malformations (BAVMs) are vascular malformations composed of tangles of abnormally developed vasculature without capillaries. Abnormal shunting of arteries and veins is formed, resulting in high-pressure vascular channels, which potentially lead to rupture. BAVMs are generally considered a congenital disorder. But clinical evidence regarding involution, regrowth, and de novo formation argue against the static condition of this disease. Recently, the presence of the somatic activating KRAS mutations in more than half of BAVM cases was reported, suggesting the role of KRAS function in the pathogenesis.MethodsKRAS mutation in codon35 (G→A, G12D; G→T, G12V) was examined by a digital polymerase chain reaction analysis using genome purified from paraffin-embedded slides of human BAVMs. We also examined protein expression of KRAS G12D in lesions to corroborate results from digital polymerase chain reaction analysis.ResultsWe detected codon35 G→A mutation in 15 (39.5%) among 38 samples and codon35 G→T mutation in 10 (27.0%) among 37 samples we could assess mutations. There were no samples positive for both codon35 G→A and G→T mutation. The ratio of codon35 G→A mutation ranged from 0.60% to 12.28% and that of G→T was from 1.20% to 8.99%. We next examined protein expression of KRAS G12D in BAVM lesions in immunohistochemistry. A KRAS G12D mutant was detected mainly in endothelial cells of dilated vessels in lesions.ConclusionsKRAS mutations in codon35 were detected in about two thirds of specimens examined. KRAS function may actively contribute to the pathobiology of BAVM and can become a therapeutic target.Copyright © 2019 Elsevier Inc. All rights reserved.

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