Breaking News
December 12, 2018 - Researchers uncover a number of previously unknown insecticide resistance mechanisms
December 12, 2018 - Regulating the immune system’s ‘regulator’
December 12, 2018 - In breaking bad news, the comfort of silence
December 12, 2018 - Study finds upward link between alcohol consumption and physical activity in college students
December 12, 2018 - FDA issues warning letter to Zhejiang Huahai Pharmaceutical involved in valsartan recall
December 12, 2018 - Presence of antiphospholipid antibodies tied to first-time MI
December 12, 2018 - New study could help inform research on preventing falls
December 12, 2018 - Women and men with heart attack symptoms receive different care from EMS
December 12, 2018 - Disrupted biological clock can contribute to onset of diseases, USC study shows
December 12, 2018 - New publications generate controversy over the value of reducing salt consumption in populations
December 12, 2018 - New data from TAILORx trial confirms lack of chemo benefit regardless of race or ethnicity
December 12, 2018 - Specific class of biomarkers can accurately indicate the severity of cancer
December 12, 2018 - Meds Taken Do Not Vary With ADL Impairment in Heart Failure
December 12, 2018 - Long-term study shows that HIV-2 is deadlier than previously thought
December 12, 2018 - People living near oil and gas wells show early signs of cardiovascular disease
December 12, 2018 - IONTAS founder and pioneer in phage display technology attends Nobel Prize Award Ceremony
December 12, 2018 - People who eat red meat have high levels of chemical associated with heart disease, study finds
December 12, 2018 - New method uses water molecules to unlock neurons’ secrets
December 12, 2018 - New computer model predicts prostate cancer progression
December 12, 2018 - Nobel Laureates lecture about immune checkpoint therapy for cancer treatment
December 12, 2018 - More Illnesses From Tainted Romaine Lettuce Reported
December 12, 2018 - Aspirin could reduce HIV infections in women
December 12, 2018 - The EORTC Brain Tumor Group and Protagen AG collaborate to study immuno-competence of long-term glioblastoma survivors
December 12, 2018 - Insights into magnetotactic bacteria could guide development of biological nanorobots
December 12, 2018 - Sacrificial immune cells alert body to infection
December 12, 2018 - Low-salt diet may be more beneficial for females than males
December 12, 2018 - Major soil organic matter compound battles chronic wasting disease
December 12, 2018 - Findings may open up new ways to treat dwarfism and other ER-stress-related conditions
December 12, 2018 - New computational model provides clearer picture of shape-changing cells’ structure and mechanics
December 12, 2018 - 10 Facts on Patient Safety
December 12, 2018 - Poorest dying nearly 10 years younger than the rich in ‘deeply worrying’ trend for UK
December 12, 2018 - Innovative care model for children with ASD reduces use of behavioral drugs in ED
December 12, 2018 - Spending time in and around Hong Kong’s waters linked to better health and wellbeing
December 12, 2018 - Simple measures to prevent weight gain over Christmas
December 12, 2018 - Research advances offer hope for patient-tailored AML treatment
December 12, 2018 - Researchers discover a ‘blind spot’ in atomic force microscopy
December 12, 2018 - Sprayable gel could help prevent recurrences of cancer after surgery
December 12, 2018 - SLU researchers explore how fetal exposure to inflammation can alter immunity in newborns
December 12, 2018 - How do patients want to discuss symptoms with clinicians?
December 12, 2018 - Zinc chelation may be able to deliver drug to insulin-producing cells
December 12, 2018 - Brigham researchers develop automated, low-cost tool to predict a woman’s ovulation
December 12, 2018 - Some people with Type 2 diabetes may be testing their blood sugar more often than needed
December 12, 2018 - Slow-growing type of glioma may be vulnerable to immunotherapy, suggests study
December 12, 2018 - Study provides new information regarding microRNA function in cellular homeostasis of zebrafish
December 12, 2018 - Study provides new understanding of mysterious ‘hereditary swelling’
December 12, 2018 - Researchers shed new light on how to combat Shiga and ricin toxins
December 12, 2018 - Pregnant Women Commonly Refuse Vaccines
December 12, 2018 - Drug treatment could offer new hope for some patients with brain bleeding
December 12, 2018 - Health care financial burden of animal-related injuries is growing, study says
December 12, 2018 - Macrophage cells could help repair the heart following a heart attack, study finds
December 12, 2018 - Researchers develop new system for efficiently producing human norovirus
December 12, 2018 - New artificial intelligence-based system to differentiate between different types of cancer cells
December 11, 2018 - Brazilian professors propose guidelines for therapeutic use of melatonin
December 11, 2018 - Healthy Lifestyle Lowers Odds of Breast Cancer’s Return
December 11, 2018 - New research identifies two genes linked to serious congenital heart condition
December 11, 2018 - NIH Director talks science, STEM careers with preteens
December 11, 2018 - Disabling a Cellular Antivirus System Could Improve Gene Therapy
December 11, 2018 - New tool swiftly provides accurate measure of patients’ cognitive difficulties
December 11, 2018 - NICE releases new guidelines for diagnosis and management of COPD
December 11, 2018 - Without Obamacare penalty, think it’ll be nice to drop your plan? Better think twice
December 11, 2018 - Researchers capture high-resolution X-ray and NMR image of key immune regulator
December 11, 2018 - Natural flavonoid is effective at treating leishmanisis infections, study shows
December 11, 2018 - Avoidant grievers unconsciously monitor and block mind-wandering contents, study shows
December 11, 2018 - Study identifies how hantaviruses infect lung cells
December 11, 2018 - Improving PTSD care through genetics
December 11, 2018 - Dermatology providers show interest in recommending cannabinoids to patients
December 11, 2018 - Researchers to study effects of electroconvulsive therapy on Alzheimer’s patients with aggression
December 11, 2018 - Four dried fruits have lower glycemic index than starchy foods, study finds
December 11, 2018 - Optimization of drug dose sizes can reduce pharmaceutical wastage
December 11, 2018 - Ultrarestrictive opioid prescribing strategy linked with reduction in number of pills dispensed
December 11, 2018 - PET scans to optimize tuberculosis meningitis treatments and personalize care, study finds
December 11, 2018 - Researchers aim to identify and target high blood pressure indicators
December 11, 2018 - Researchers identify immune cell subset that may drive chronic inflammation
December 11, 2018 - Ezogabine treatment reduces motor neuron excitability in ALS patients, study shows
December 11, 2018 - One implant, two prices. It depends on who’s paying.
December 11, 2018 - Standardizing feeding practices improves growth trends for micro-preemies
December 11, 2018 - COPD Tied to Obesity in Male, Female Never-Smokers
December 11, 2018 - Flossing: Information for Caregivers
December 11, 2018 - Does breastfeeding hormone protect against type 2 diabetes?
December 11, 2018 - Educating future doctors to prescribe physical activity for their patients
Genetic Mutation May Underlie AV Malformations

Genetic Mutation May Underlie AV Malformations

image_pdfDownload PDFimage_print

Action Points

  • Note that this observational study found a high rate of KRAS mutations in tissue samples of brain arteriovenous malformations.
  • Be aware that these mutations were not detected in peripheral blood, suggesting they are acquired at some point during life.

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.

  • Reviewed by
    F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

2018-01-04T09:15:00-0500

Tagged with:

About author

Related Articles