High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations

Hong, Tao; Yan, Yupeng; Li, Jingwei; Radovanović, Ivan; Ma, Xiongfeng; Shao, Yang; Yu, Jiaxing; Ma, Yan; Zhang, Peng; Li, Feng; Huang, Shuchen; Zhang, Hongqi; Wang, Yibo

doi:10.1093/brain/awy307

Cited by 126 publications

(120 citation statements)

References 42 publications

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“…The studies described above (35,36) did not find a difference in affected tissue VAF between disease groups, but Kuentz et al found increased VAF in affected tissue compared with blood and increased VAF in blood in patients with brain overgrowth compared with those with only body overgrowth. A recent study on arteriovenous malformations (AVMs) with mosaic KRAS and BRAF mutations found a negative correlation between VAF and AVM nidus size, with larger AVMs associated with lower VAFs (38). These studies did not, however, provide analysis of affected gene or individual mutations and their relationship to VAF.…”

Section: Discussionmentioning

confidence: 96%

Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations

Zenner¹,

Cheng²,

Jensen³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 96%

Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations

Zenner¹,

Cheng²,

Jensen³

et al. 2019

JCI Insight

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“…Abbreviations consequences, including overgrowth, brain malformations, vascular malformations, and skin pigment abnormalities. 4,[20][21][22] Twelve individuals in our cohort had activating GNA11 (MIM: 139313) p.Arg183Cys variants and seven had activating GNAQ (MIM: 600998) p.Arg183Gln variants; all of these had some form of vascular malformation and many had tissue overgrowth as well. 22 Eleven individuals had P/LP variants in KRAS (MIM: 190070, Figure 4B), seven were present at the canonical p.Gly12 position.…”

Section: Clinically Relevant Findingsmentioning

confidence: 92%

Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort

McNulty

Evenson

Corliss

et al. 2019

The American Journal of Human Genetics

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Disorders of somatic mosaicism (DoSM) are a diverse group of syndromic and non-syndromic conditions caused by mosaic variants in genes that regulate cell survival and proliferation. Despite overlap in gene space and technical requirements, few clinical labs specialize in DoSM compared to oncology. We adapted a high-sensitivity next-generation sequencing cancer assay for DoSM in 2014. Some 343 individuals have been tested over the past 5 years, 58% of which had pathogenic and likely pathogenic (P/LP) findings, for a total of 206 P/LP variants in 22 genes. Parameters associated with the high diagnostic yield were: (1) deep sequencing (2,0003 coverage), (2) a broad gene set, and (3) testing affected tissues. Fresh and formalin-fixed paraffin embedded tissues performed equivalently for identification of P/LP variants (62% and 71% of individuals, respectively). Comparing cultured fibroblasts to skin biopsies suggested that culturing might boost the allelic fraction of variants that confer a growth advantage, specifically gain-of-function variants in PIK3CA. Buccal swabs showed high diagnostic sensitivity in case subjects where disease phenotypes manifested in the head or brain. Peripheral blood was useful as an unaffected comparator tissue to determine somatic versus constitutional origin but had poor diagnostic sensitivity. Descriptions of all tested individuals, specimens, and P/LP variants included in this cohort are available to further the study of the DoSM population.

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“… 8 Activating mutations have also been identified in BRAF and MAP2K1/MEK ( mitogen-activated protein kinase kinase 1) in AVMs. 6 , 7 Each of these mutated genes function in the MEK/ERK (extracellular signal-regulated kinase) kinase cascade, suggesting this pathway plays a key role in AVM pathogenesis. Indeed, we observed robust MEK/ERK activity in all bAVM tissues that we examined, even those that did not contain detectable KRAS mutations, indicating that excessive activity of this pathway is a central feature in the pathogenesis of these lesions.…”

mentioning

confidence: 99%

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

Fish

Flores-Suarez

Boudreau

et al. 2020

Circulation Research

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Rationale: We previously identified somatic activating mutations in the KRAS gene in the endothelium of the majority of human sporadic brain arteriovenous malformations (bAVMs); a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to AVM formation, remains unknown. Objective: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish in order to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for AVMs. Methods and Results: Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce bAVMs. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity, but instead appear to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent AVMs in zebrafish are refractory to inhibition of the downstream effector PI3K, but instead require active MEK signaling. Conclusions: We demonstrate that active KRAS expression in the endothelium is sufficient for bAVM formation, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for AVM patients.

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High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations

Cited by 126 publications

References 42 publications

Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations

Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations

Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

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