Activating KRAS mutations in arteriovenous malformations of the brain: frequency and clinicopathologic correlation

Priemer, David S.; Vortmeyer, Alexander O.; Zhang, Shaobo; Chang, Hsim Y.; Curless, Kendra

doi:10.1016/j.humpath.2019.04.004

Cited by 53 publications

(62 citation statements)

References 27 publications

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“…We were unable to identify obvious clinical, radiographic, or histologic features that can be used to predict whether a patient who has a sporadic AVM will have a detectable versus undetectable somatic mutation, or a KRAS versus a BRAF mutation. Our data are similar to those of Priemer et al (2019) who also did not find differences in patient characteristics (age, size, and gender) between those with and without KRAS mutations [11]. These findings are biased toward resectable AVMs (e.g., brain stem lesions may not be removable).…”

Section: Discussionsupporting

confidence: 90%

“…After collapsing smMIPs with the same barcode, we achieved > 150-fold coverage for 85% of the protein coding sequences for KRAS , BRAF , HRAS , NRAS , and MAP2K1 . Because KRAS codon p.12G and BRAF codon p.600V somatic mutations have been linked to brain AVMs [9–11], we obtained > 500-fold coverage for these regions of each gene in all 16 specimens, and >5,000-fold coverage in 15/16 AVM specimens. Thus, for most AVM specimens we could detect a MAF as low as 0.04% at these codons.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, Hong et al considered some of their ddPCR result positives with a MAF as low as 0.03% [10]. Priemer et al (2019) tested DNA from formalin-fixed, paraffin-embedded (FFPE) tissue blocks from brain AVMs for 7 common cancer-associated KRAS mutations (including p.G12D and p.G12V) and found mutations in 6/21 cases (29%) [11]. Their use of FFPE extracted DNA and an assay that loses sensitivity for a MAF < 1% may account for the lower detection rate in that study [11].…”

Section: Discussionmentioning

confidence: 99%

“…However, almost all intracranial AVMs are non-hereditary and sporadic. Somatic KRAS mutations have been identified in the majority of brain AVM specimens [9–11]. The purpose of this study was to identify novel mutations in intracranial AVMs and to determine whether a genotype-phenotype correlation exists.…”

Section: Introductionmentioning

confidence: 99%

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Somatic mutations in intracranial arteriovenous malformations

et al. 2019

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BackgroundIntracranial arteriovenous malformation (AVM) is a common cause of primary intracerebral hemorrhage in young adults. Lesions typically are sporadic and contain somatic mutations in KRAS or BRAF. The purpose of this study was to identify somatic mutations in a cohort of participants with brain AVM and to determine if any genotype-phenotype associations exist.MethodsHuman brain AVM specimens (n = 16) were collected during a clinically-indicated procedure and subjected to multiplex targeted sequencing using molecular inversion probe (MIP-seq) for mutations in KRAS, BRAF, HRAS, NRAS, and MAP2K1. Endothelial cells (ECs) were separated from non-ECs by immune-affinity purification. Droplet digital PCR (ddPCR) was used to confirm mutations and to screen for mutations that may have been missed by MIP-seq. Patient and AVM characteristics were recorded.ResultsWe detected somatic mutations in 10 of 16 specimens (63%). Eight had KRAS mutations [G12D (n = 5), G12V (n = 3)] and two had BRAF mutations [V600E (n = 1), Q636X (n = 1)]. We found no difference in age, sex, presenting symptom, AVM location, or AVM size between patients with a confirmed mutation and those without. Nor did we observe differences in these features between patients with KRAS or BRAF mutations. However, two patients with BRAF mutations presented at an older age than other study participants.ConclusionsSomatic mutations in KRAS and, less commonly in BRAF, are found in many but not all intracranial AVM samples. Currently, there are no obvious genotype-phenotype correlations that can be used to predict whether a somatic mutation will be detected and, if so, which gene will be mutated.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Somatic mutations in intracranial arteriovenous malformations

et al. 2019

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“…However, this was expected as our analysis was performed on DNA purified by peripheral blood. Mosaic-activating KRAS mutations, indeed, were found in sporadic AVM-derived specimens [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis

Scimone

Granata

Longo

et al. 2020

IJMS

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Brain arteriovenous malformation (bAVM) is a congenital defect affecting brain microvasculature, characterized by a direct shunt from arterioles to venules. Germline mutations in several genes related to transforming growth factor beta (TGF-β)/BMP signaling are linked to both sporadic and hereditary phenotypes. However, the low incidence of inherited cases makes the genetic bases of the disease unclear. To increase this knowledge, we performed a whole exome sequencing on five patients, on DNA purified by peripheral blood. Variants were filtered based on frequency and functional class. Those selected were validated by Sanger sequencing. Genes carrying selected variants were prioritized to relate these genes with those already known to be linked to bAVM development. Most of the prioritized genes showed a correlation with the TGF-βNotch signaling and vessel morphogenesis. However, two novel pathways related to cilia morphogenesis and ion homeostasis were enriched in mutated genes. These results suggest novel insights on sporadic bAVM onset and confirm its genetic heterogeneity. The high frequency of germline variants in genes related to TGF-β signaling allows us to hypothesize bAVM as a complex trait resulting from the co-existence of low-penetrance loci. Deeper knowledge on bAVM genetics can improve personalized diagnosis and can be helpful with genotype–phenotype correlations.

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Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice

Park

Kim

Huang³

et al. 2021

Annals of Neurology

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Objective: Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRAS G12V mutation induces sporadic bAVMs in mice. Methods: Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRAS G12V . At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRAS G12V -induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor. Results: The viral-mediated KRAS G12V overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment. Interpretation: Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM.

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Activating KRAS mutations in arteriovenous malformations of the brain: frequency and clinicopathologic correlation

Cited by 53 publications

References 27 publications

Somatic mutations in intracranial arteriovenous malformations

Somatic mutations in intracranial arteriovenous malformations

Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis

Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice

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