Arteriovenous malformations of the brain may arise due to a genetic mutation, acquired later in life, that activates a cellular signaling pathway in endothelial cells — the same one that drives tumor formation, a study showed.
Often the root of hemorrhagic stroke in young adults and children, these abnormal connections between arteries and veins in the brain vasculature were sampled via temporal lobectomy, after which exome DNA sequencing detected somatic activating KRAS mutations in 45 out of 72 tissue samples.
Researchers led by Sergey Nikolaev, PhD, of University of Geneva Medical School, reported in the New England Journal of Medicine that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased extracellular signal-regulated kinase (ERK) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. Inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling reversed these processes.
“We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells,” Nikolaev’s group wrote, suggesting that active KRAS “dysregulates angiogenesis and vascular remodeling in endothelial cells.”
“How might alterations in RAS signaling in endothelial cells induce arteriovenous malformations? The mutations that we have identified are known to drive strong and constitutive MAPK-ERK signaling and are important drivers of tumorigenesis. Arteriovenous malformations of the brain are not associated with cancer, which suggests a context-dependent role for KRAS mutations in the endothelium. The finding that somatic activating KRAS mutations in endometriosis do not cause cancer is consistent with this interpretation.”
Even if not all arteriovenous malformation samples showed activating KRAS mutations, they still had more MAPK-ERK signaling in endothelial cells. This led the investigators to conclude that activation of this pathway may be a defining feature of these malformations.
“In the absence of available direct pharmacologic inhibitors of KRAS, small-molecule MEK inhibitors, which are used in clinical practice for treating cancers, represent candidates for testing in clinical trials to treat arteriovenous malformations of the brain,” the authors suggested.
Nikolaev and colleagues conducted their study using tissue and blood samples from 72 patients with arteriovenous malformations, a group comprising patients from Canada’s Toronto Western Hospital and an independent validation group from Finland.
Participants were eligible if they had unifocal arteriovenous malformations with a defined nidus and arteriovenous shunting found on digital subtraction angiography. Additionally, they couldn’t have a family history of arteriovenous malformations or documented history of genetic vascular disease.
“The causal mutations here are acquired in life and only present in the diseased tissue,” emphasized Sekar Kathiresan, MD, of Massachusetts General Hospital, who was not involved with the study, explaining that these KRAS mutations therefore “cannot be tested for from a blood sample.”
Indeed, the study authors found no KRAS mutations in patients’ blood.
“I would not recommend genetic testing for patients based on this finding alone,” said Shyam Prabhakaran, MD, of Northwestern Memorial Hospital in Chicago, who also was not involved with the study. He added that there is no prognostic or treatment implication yet, anyway.
It will be necessary to replicate the present data given that they come from such a limited sample, Prabhakaran said. “Further studies could consider whether this mutation or dysregulation of the RAS-MAPK pathway is associated with arteriovenous malformation growth or rupture.”
Nevertheless, the findings by Nikolaev’s group are “truly novel,” according Kathiresan. “Now, one can basically think of this disease like a cancer of blood vessel lining cells. The finding suggests a treatment hypothesis as well — inhibiting the KRAS pathway may prevent growth of these malformations.”
“This finding builds on an emerging theme of acquired mutations as a cause of common diseases,” he continued. His own research group recently found that acquired mutations in blood stem cells increase the risk of heart attack.
Nikolaev reported grants from the Swiss Cancer League, Dinu Lipatti, and Novartis over the course of the study.
Kathiresan and Prabhakaran disclosed no relevant conflicts of interest.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner