Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations

Tu, Tianqi; Yu, Jiaxing; Jiang, Chendan; Zhang, Shikun; Li, Jingwei; Ren, Jian; Zhang, Shiju; Zhou, Yuan; Cui, Ziwei; Lu, Haohan; Meng, Xiaosheng; Wang, Zhanjing; Xing, Dong; Zhang, Hongqi; Hong, Tao

doi:10.1007/s10456-024-09918-8

Angiogenesis

2024

DOI: 10.1007/s10456-024-09918-8

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Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations

Tianqi Tu,

Jiaxing Yu,

Chendan Jiang

et al.

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Cited by 3 publications

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Cerebral vascular malformations: pathogenesis and therapy

He,

Huo,

Sun

et al. 2024

MedComm

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Cerebral vascular malformations (CVMs), particularly cerebral cavernous malformations and cerebral arteriovenous malformations, pose significant neurological challenges due to their complex etiologies and clinical implications. Traditionally viewed as congenital conditions with structural abnormalities, CVMs have been treated primarily through resection, embolization, and stereotactic radiosurgery. While these approaches offer some efficacy, they often pose risks to neurological integrity due to their invasive nature. Advances in next‐generation sequencing, particularly high‐depth whole‐exome sequencing and bioinformatics, have facilitated the identification of gene variants from neurosurgically resected CVMs samples. These advancements have deepened our understanding of CVM pathogenesis. Somatic mutations in key mechanistic pathways have been identified as causative factors, leading to a paradigm shift in CVM treatment. Additionally, recent progress in noninvasive and minimally invasive techniques, including gene imaging genomics, liquid biopsy, or endovascular biopsies (endovascular sampling of blood vessel lumens), has enabled the identification of gene variants associated with CVMs. These methods, in conjunction with clinical data, offer potential for early detection, dynamic monitoring, and targeted therapies that could be used as monotherapy or adjuncts to surgery. This review highlights advancements in CVM pathogenesis and precision therapies, outlining the future potential of precision medicine in CVM management.

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Cerebral vascular malformations: pathogenesis and therapy

He,

Huo,

Sun

et al. 2024

MedComm

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Inhibition of Angiopoietin-2 rescues sporadic brain arteriovenous malformations by reducing pericyte loss

Tu,

Zhang,

et al. 2024

Angiogenesis

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Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT)

Whitehead,

Toydemir,

Wooderchak-Donahue

et al. 2024

IJMS

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Telangiectases and arteriovenous malformations (AVMs) are the characteristic lesions of Hereditary Hemorrhagic Telangiectasia (HHT). Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1, have been described in dermal telangiectasias. It is unclear if somatic second-hit mutations also cause the formation of AVMs and nasal telangiectasias in HHT. To investigate the genetic mechanism of AVM formation in HHT, we evaluated multiple affected tissues from fourteen individuals. DNA was extracted from fresh/frozen tissue of 15 nasal telangiectasia, 4 dermal telangiectasia, and 9 normal control tissue biopsies, from nine unrelated individuals with HHT. DNA from six formalin-fixed paraffin-embedded (FFPE) AVM tissues (brain, lung, liver, and gallbladder) from five individuals was evaluated. A 736 vascular malformation and cancer gene next-generation sequencing (NGS) panel was used to evaluate these tissues down to 1% somatic mosaicism. Somatic second-hit mutations were identified in three in four AVM biopsies (75%) or half of the FFPE (50%) samples, including the loss of heterozygosity in ENG in one brain AVM sample, in which the germline mutation occurred in a different allele than a nearby somatic mutation (both are loss-of-function mutations). Eight of nine (88.9%) patients in whom telangiectasia tissues were evaluated had a somatic mutation ranging from 0.68 to 1.96% in the same gene with the germline mutation. Six of fifteen (40%) nasal and two of four (50%) dermal telangiectasia had a detectable somatic second hit. Additional low-level somatic mutations in other genes were identified in several telangiectasias. This is the first report that nasal telangiectasias and solid organ AVMs in HHT are caused by very-low-level somatic biallelic second-hit mutations.

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Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations

Cited by 3 publications

References 60 publications

Cerebral vascular malformations: pathogenesis and therapy

Cerebral vascular malformations: pathogenesis and therapy

Inhibition of Angiopoietin-2 rescues sporadic brain arteriovenous malformations by reducing pericyte loss

Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT)

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