Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

Abstract

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...

Clinical and genetic findings in children with central nervous system arteriovenous fistulas

“…42 No cutaneous lesions were observed in sporadic cases with no identified mutation, in contrast to cases with HHT or a CM-AVM1 mutation. 7,41 A second somatic genetic hit on the wild-type allele has been observed, which would account for the localized lesions observed in CM-AVM1.…”

“…7,41 A second somatic genetic hit on the wild-type allele has been observed, which would account for the localized lesions observed in CM-AVM1. 42 No cutaneous lesions were observed in sporadic cases with no identified mutation, in contrast to cases with HHT or a CM-AVM1 mutation. Several hypotheses can be proposed.…”

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

“…Among them are RASopathies, which include the Noonan, Costello and cardio-facio-cutaneous (CFC) syndromes [103, 104], extracranial arteriovenous malformation [105], and Kabuki syndrome [106]. These last disorders can be induced by activating the mutation of MEK (CFC) or upstream components of the ERK1/2 cascade [107].…”

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

“…In sharp contrast to unaffected cortical bone, affected osteonal‐like bone exhibits abundant osteoclasts, osteoblasts, excessive osteoid formation, and high porosity. Consistently, the number of vascular channels in the lesions was shown by micro‐CT to be markedly elevated, suggesting that angiogenesis might also play an important role in the pathophysiology of melorheostosis, as it does in tumors caused by hyperactivation of the MEK1‐ERK1/2 pathway or in extracranial arteriovenous malformation . Although the median pore diameter of 50 μm, corresponding to the typical size of Haversian channels, was similar in affected and unaffected bone, enlarged vascular spaces with multiple blood vessels were also often viewed in melorheostotic bone .…”

“…Consistently, the number of vascular channels in the lesions was shown by micro-CT to be markedly elevated, suggesting that angiogenesis might also play an important role in the pathophysiology of melorheostosis, as it does in tumors caused by hyperactivation of the MEK1-ERK1/2 pathway or in extracranial arteriovenous malformation. (26,27) Although the median pore diameter of 50 mm, corresponding to the typical size of Haversian channels, was similar in affected and unaffected bone, enlarged vascular spaces with multiple blood vessels were also often viewed in melorheostotic bone. (12) However, there is a notable difference in the orientation of the channels: in unaffected bone, we observed a predominant alignment of the Haversian channels and concomitantly osteons along the longitudinal axis of the bone.…”