Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.
Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.
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DOI：
10.1172/jci98589
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发表时间：
2018-04-02
期刊：
影响因子：
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通讯作者：
Kinsler VA
中科院分区：
文献类型：
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作者：
Al-Olabi L;Polubothu S;Dowsett K;Andrews KA;Stadnik P;Joseph AP;Knox R;Pittman A;Clark G;Baird W;Bulstrode N;Glover M;Gordon K;Hargrave D;Huson SM;Jacques TS;James G;Kondolf H;Kangesu L;Keppler-Noreuil KM;Khan A;Lindhurst MJ;Lipson M;Mansour S;O'Hara J;Mahon C;Mosica A;Moss C;Murthy A;Ong J;Parker VE;Rivière JB;Sapp JC;Sebire NJ;Shah R;Sivakumar B;Thomas A;Virasami A;Waelchli R;Zeng Z;Biesecker LG;Barnacle A;Topf M;Semple RK;Patton EE;Kinsler VA
背景。散发性血管畸形 (VM) 是一种复杂的先天性血管异常，可导致中风、危及生命的出血、毁容、过度生长和/或疼痛。治疗选择非常有限，多学科治疗仍然具有挑战性，特别是对于高流量动静脉畸形（AVM）。方法。为了研究排除已知遗传原因的 160 名儿童散发性颅内和颅外 VM 的发病机制，我们对受影响组织的 DNA 进行了测序，并优化了分析以检测低突变等位基因频率。结果。我们在 RAS/MAPK 通路的 4 个基因（KRAS、NRAS、BRAF 和 MAP2K1）中发现了多个嵌合激活变异，MAP2K1 是癌症中常见的激活通路，导致种系 RAS 疾病。这些变体在高流量虚拟机中比在低流量虚拟机中更常见。体外表征和 2 个再现人类表型的转基因斑马鱼 AVM 模型验证了突变等位基因的发病机制。重要的是，用 BRAF 抑制剂维罗非尼治疗 AVM-BRAF 突变斑马鱼可以恢复 AVM 的血流。结论。我们的研究结果揭示了不同临床类型散发性 VM 的主要原因，从而通过重新利用现有许可的癌症疗法提供个性化医疗的潜力。资金。这项工作得到了 AVM Butterfly 慈善机构、Wellcome Trust（英国）、医学研究委员会（英国）、英国国家健康研究所、欧莱雅黑色素瘤研究联盟、欧洲研究委员会和国家人类基因组研究所（美国）的资助或支持。
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. FUNDING. This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L’Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).