TY - JOUR
T1 - Somatic activating KRAS mutations in arteriovenous malformations of the brain
AU - Nikolaev, S. I.
AU - Vetiska, S.
AU - Bonilla, X.
AU - Boudreau, E.
AU - Jauhiainen, S.
AU - Rezai Jahromi, B.
AU - Khyzha, N.
AU - Di Stefano, P. V.
AU - Suutarinen, S.
AU - Kiehl, T. R.
AU - Mendes Pereira, V.
AU - Herman, A. M.
AU - Krings, T.
AU - Andrade-Barazarte, H.
AU - Tung, T.
AU - Valiante, T.
AU - Zadeh, G.
AU - Tymianski, M.
AU - Rauramaa, T.
AU - Ylä-Herttuala, S.
AU - Wythe, J.
AU - Antonarakis, S. E.
AU - Frösen, J.
AU - Fish, J. E.
AU - Radovanovic, I.
N1 - Publisher Copyright:
© Copyright 2018 Massachusetts Medical Society.
PY - 2018/1/18
Y1 - 2018/1/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040949986&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1709449
DO - 10.1056/NEJMoa1709449
M3 - Article
C2 - 29298116
AN - SCOPUS:85040949986
SN - 0028-4793
VL - 378
SP - 250
EP - 261
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 3
ER -