Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy

被引：199

作者：

Al-Olabi, Lara ^{[1
]}

Polubothu, Satyamaanasa ^{[1
,2
]}

Dowsett, Katherine ^{[3
,4
]}

Andrews, Katrina A. ^{[5
,6
]}

Stadnik, Paulina ^{[1
]}

Joseph, Agnel P. ^{[7
]}

Knox, Rachel ^{[5
,6
]}

Pittman, Alan ^{[8
]}

Clark, Graeme ^{[9
]}

Baird, William ^{[1
]}

Bulstrode, Neil ^{[10
]}

Glover, Mary ^{[2
]}

Gordon, Kristiana ^{[11
]}

Hargrave, Darren ^{[12
]}

Huson, Susan M. ^{[13
]}

Jacques, Thomas S. ^{[14
,15
]}

James, Gregory ^{[16
]}

Kondolf, Hannah ^{[17
]}

Kangesu, Loshan ^{[10
]}

Keppler-Noreuil, Kim M. ^{[17
]}

Khan, Amjad ^{[2
]}

Lindhurst, Marjorie J. ^{[17
]}

Lipson, Mark ^{[18
]}

Mansour, Sahar ^{[19
]}

O'Hara, Justine ^{[10
]}

Mahon, Caroline ^{[2
]}

Mosica, Anda ^{[2
]}

Moss, Celia ^{[20
,21
]}

Murthy, Aditi ^{[2
]}

Ong, Juling ^{[10
]}

Parker, Victoria E. ^{[5
,6
]}

Riviere, Jean-Baptiste ^{[22
,23
]}

Sapp, Julie C. ^{[17
]}

Sebire, Neil J. ^{[24
]}

Shah, Rahul ^{[10
]}

Sivakumar, Branavan ^{[10
]}

Thomas, Anna ^{[1
]}

Virasami, Alex ^{[14
,15
]}

Waelchli, Regula ^{[2
]}

Zeng, Zhiqiang ^{[3
,4
]}

Biesecker, Leslie G. ^{[17
]}

Barnacle, Alex ^{[25
]}

Topf, Maya ^{[7
]}

Semple, Robert K. ^{[5
,6
,26
]}

Patton, E. Elizabeth ^{[3
,4
]}

Kinsler, Veronica A. ^{[1
,2
]}

机构：

[1] UCL GOS Inst Child Hlth, Genet & Genom Med, 30 Guilford St, London WC1N 1EH, England

[2] Great Ormond St Hosp Children NHS Fdn Trust, Paediat Dermatol, London, England

[3] Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[4] Univ Edinburgh, Western Gen Hosp, Canc Res UK CRUK Edinburgh Ctr, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[5] Univ Cambridge, Wellcome Trust MRC Inst Metab Sci, Metab Res Labs, Cambridge, England

[6] Natl Inst Hlth Res Cambridge Biomed Res Ctr, Cambridge, England

[7] Birkbeck Univ London, Dept Biol Sci, London, England

[8] UCL Inst Neurol, Mol Neurosci, London, England

[9] Univ Cambridge, Dept Med Genet, Cambridge Biomed Campus, Cambridge, England

[10] Great Ormond St Hosp Children NHS Fdn Trust, Plast Surg, London, England

[11] St Georges Hosp NHS Trust, Dermatol & Lymphovasc Med, London, England

[12] Great Ormond St Hosp Children NHS Fdn Trust, Paediat Oncol, London, England

[13] St Marys Hosp, Manchester Ctr Genom Med, Manchester, Lancs, England

[14] Great Ormond St Hosp Children NHS Fdn Trust, UCL Great Ormond St Inst Child Hlth, Dev Biol & Canc Programme, London, England

[15] Great Ormond St Hosp Children NHS Fdn Trust, Dept Histopathol, London, England

[16] Great Ormond St Hosp Children NHS Fdn Trust, Paediat Neurosurg, London, England

[17] NHGRI, NIH, Bethesda, MD 20892 USA

[18] Kaiser Permanente Med Ctr, Paediat & Clin Genet, Sacramento, CA USA

[19] St Georges Hosp NHS Trust, Clin Genet, London, England

[20] Birmingham Womens & Childrens NHS Fdn Trust Birmi, Paediat Dermatol, Birmingham, W Midlands, England

[21] Univ Birmingham, Birmingham, W Midlands, England

[22] McGill Univ, Ctr Hlth, Montreal, PQ, Canada

[23] McGill Univ, Res Inst, Montreal, PQ, Canada

[24] Great Ormond St Hosp Children NHS Fdn Trust, Paediat Pathol, London, England

[25] Great Ormond St Hosp Children NHS Fdn Trust, Intervent Radiol, London, England

[26] Univ Edinburgh, Ctr Cardiovasc Sci, Queens Med Res Inst, Edinburgh, Midlothian, Scotland

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2018年 / 128卷 / 04期

基金：

英国惠康基金; 欧洲研究理事会;

关键词：

CEREBRAL CAVERNOUS MALFORMATIONS; EPIDERMAL NEVUS SYNDROME; ACTIVATING MUTATIONS; ARTERIOVENOUS-MALFORMATION; OCULOECTODERMAL SYNDROME; POSTZYGOTIC MUTATIONS; KRAS MUTATION; PIK3CA CAUSE; ZEBRAFISH; GERMLINE;

D O I：

10.1172/JCI98589

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.

引用

页码：1496 / 1508

页数：13

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