Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma

Lim, Young Hee; Douglas, Stephanie R.; Ko, Christine J.; Antaya, Richard J.; McNiff, Jennifer M.; Zhou, Jing; Choate, Keith; Narayan, Deepak

doi:10.1038/jid.2015.55

Cited by 66 publications

(58 citation statements)

References 15 publications

(24 reference statements)

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“…Extramedullary hematopoiesis has been previously reported in PG, including two case reports and a retrospective review of 157 pyogenic granulomas in which 10% reportedly contained extramedullary hematopoietic elements. 5 As in our case, erythropoiesis was the dominant pattern of extramedullary hematopoiesis found, but predominantly myeloid cases occur as well. Of note, extramedullary hematopoiesis has been documented in cutaneous and nasal pyogenic granulomas but was not observed in any of 23 oral examples.…”

Section: Discussion Follows On Page 376supporting

confidence: 63%

Extramedullary Hematopoiesis in a Pyogenic Granuloma

Richey

North

2015

J Cutan Pathol

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Section: Discussion Follows On Page 376supporting

confidence: 63%

Extramedullary Hematopoiesis in a Pyogenic Granuloma

Richey

North

2015

J Cutan Pathol

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“…19 Somatic mutations affecting proteins upstream of MEK1 occur in cancer and other types of vascular malformations. 12,19,[29][30][31][32][33][34] The MAP2K1 mutations we detected in AVMs likely alter the function of MEK1 by producing a hypermorphic or neomorphic effect, since these mutations have previously been shown to increase ERK1 and ERK2 phosphorylation in tumors and in cultured cells. Consistent with this hypothesis, mice that are heterozygous for Mek1 knockout alleles do not exhibit a phenotype, whereas homozygous knockout alleles cause embryonic lethality and placental defects.…”

mentioning

confidence: 80%

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

Couto

Huang

Konczyk

et al. 2017

The American Journal of Human Genetics

236

171

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Arteriovenous malformation (AVM) is a fast-flow, congenital vascular anomaly that may arise anywhere in the body. AVMs typically progress, causing destruction of surrounding tissue and, sometimes, cardiac overload. AVMs are difficult to control; they often re-expand after embolization or resection, and pharmacologic therapy is unavailable. We studied extracranial AVMs in order to identify their biological basis. We performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) on AVM tissue from affected individuals. Endothelial cells were separated from non-endothelial cells by immune-affinity purification. We used droplet digital PCR (ddPCR) to confirm mutations found by WES and WGS, to determine whether mutant alleles were enriched in endothelial or non-endothelial cells, and to screen additional AVM specimens. In seven of ten specimens, WES and WGS detected and ddPCR confirmed somatic mutations in mitogen activated protein kinase kinase 1 (MAP2K1), the gene that encodes MAP-extracellular signal-regulated kinase 1 (MEK1). Mutant alleles were enriched in endothelial cells and were not present in blood or saliva. 9 of 15 additional AVM specimens contained mutant MAP2K1 alleles. Mutations were missense or small in-frame deletions that affect amino acid residues within or adjacent to the protein's negative regulatory domain. Several of these mutations have been found in cancers and shown to increase MEK1 activity. In summary, somatic mutations in MAP2K1 are a common cause of extracranial AVM. The likely mechanism is endothelial cell dysfunction due to increased MEK1 activity. MEK1 inhibitors, which are approved to treat several forms of cancer, are potential therapeutic agents for individuals with extracranial AVM.Arteriovenous malformation (AVM) is a congenital vascular anomaly, comprised of abnormal connections between arteries and veins that are missing normal high-resistance capillary beds (Figure 1). 1 Sporadic extracranial AVMs are solitary and may be localized or regional. Rapid blood flow is demonstrable by Doppler ultrasonography. Magnetic resonance imaging reveals signal voids consistent with fast-flow, while angiography shows the early filling of draining veins (Figure 1). With time, arterial to venous shunting causes tissue ischemia that leads to pain, ulceration, bleeding, and destruction of adjacent tissues. Treatment for AVM has been discouraging. Embolization and/or resection are often followed by expansion; there are no drug treatments. 2 The purpose of this study was to identify the genetic basis for sporadic, extracranial AVM in an effort to devise a new therapeutic strategy.The Committee on Clinical Investigation at Boston Children's Hospital approved this study and informed consent was obtained from study participants. Ten AVM specimens that had been collected during a clinically indicated procedure, including matched unaffected tissue specimens from three of the study participants, had DNA extracted using the DNeasy Blood & Tissue Kit (QIAGEN); saliva DNA was extracted using the pr...

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“…6,7 Most recently, somatic activating RAS mutations have also been delineated in certain vascular tumours, including pyogenic granuloma. 8 Clinically, at the age of 6 months, this child continues to show no overt neurological, ocular or skeletal abnormalities. No anomalies have been detected on imaging, notwithstanding reports of the low detection of neuropathology by computerised tomography or MRI, even in naevus sebaceus patients with clinical neurological abnormalities.…”

Section: Patientmentioning

confidence: 89%

Systematised naevus sebaceus resulting from post‐zygotic mutation in HRAS

et al. 2015

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The microbiome and atopic eczema: More than skin deep Charlotte L Thomas and Pablo Fernández-Peñas 18 ORIGINAL RESEARCH Skin protection behaviour and sex differences in melanoma location in patients with multiple primary melanomas Matthew Warren, Erin McMeniman, Agnieszka Adams and Brian De'Ambrosis 25 A clinical audit of high-cost and off-label drug use in dermatology Natalie Ong, Erin McMeniman, Peter Pillans and H Peter Soyer 30 Chemotherapy compliance in high-risk M erkel cell carcinoma treated with chemoradiotherapy Peter Gorayski, Lee Tripcony and Michael Poulsen 35 CASE REPORTS Carotenemia and hepatomegaly in an atopic child on an exclusion diet for a food allergy Arun Gangakhedkar, Rebecca Somerville and Timothy Jelleyman 42 Macular pigmentation of uncertain aetiology revisited: two case reports and a proposed algorithm for clinical classification Veena Chandran and Sujith Prasad Kumarasinghe 45 DERMOSCOPY Dermoscopic features of a case of transient acantholytic dermatosis

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Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma

Cited by 66 publications

References 15 publications

Extramedullary Hematopoiesis in a Pyogenic Granuloma

Extramedullary Hematopoiesis in a Pyogenic Granuloma

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

Systematised naevus sebaceus resulting from post‐zygotic mutation in HRAS

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