Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation
Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation
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DOI：
10.1016/j.ajhg.2017.01.018
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发表时间：
2017-03-02
影响因子：
9.8
通讯作者：
Greenel, Arin K.
中科院分区：
文献类型：
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作者：
Couto, Javier A.;Huang, August Y.;Greenel, Arin K.
动静脉畸形（AVM）是一种快速流动的先天性血管异常，可发生在身体的任何地方。AVM通常进展，导致周围组织破坏，有时导致心脏超负荷。AVM很难控制;栓塞或切除后经常再次扩张，且无法进行药物治疗。我们研究了颅外AVM，以确定其生物学基础。我们对受影响个体的AVM组织进行了全外显子组测序（WES）和全基因组测序（WGS）。通过免疫亲和纯化将内皮细胞与非内皮细胞分离。我们使用液滴数字PCR（ddPCR）来确认WES和WGS发现的突变，以确定突变等位基因是否在内皮细胞或非内皮细胞中富集，并筛选其他AVM标本。在10份标本中的7份中，WES和WGS检测到并通过ddPCR证实了丝裂原活化蛋白激酶激酶1（MAP 2K 1）的体细胞突变，该基因编码MAP-细胞外信号调节激酶1（MEK 1）。突变等位基因在内皮细胞中富集，而在血液或唾液中不存在。15份额外AVM标本中有9份含有突变的MAP 2K 1等位基因。突变是错义或小的框内缺失，其影响蛋白质的负调控结构域内或附近的氨基酸残基。这些突变中的几个已经在癌症中发现，并显示出增加MEK 1活性。总之，MAP 2K 1的体细胞突变是颅外AVM的常见原因。可能的机制是由于MEK 1活性增加导致的内皮细胞功能障碍。被批准用于治疗多种癌症的MEK 1抑制剂是颅外AVM患者的潜在治疗药物。
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.