Somatic Activating PIK3CA Mutations Cause Venous Malformation
Somatic Activating PIK3CA Mutations Cause Venous Malformation
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DOI：
10.1016/j.ajhg.2015.11.011
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发表时间：
2015-12-01
影响因子：
9.8
通讯作者：
Vikkula, Miikka
中科院分区：
文献类型：
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作者：
Limaye, Nisha;Kangas, Jaakko;Vikkula, Miikka
TEK（编码内皮细胞酪氨酸激酶受体TIE 2的基因）的体细胞突变导致超过一半的偶发性单灶性静脉畸形（VM）。在这里，我们报告了PIK 3CA（编码PI 3 K催化p110 α亚基的基因）的体细胞突变导致54%（50例中的27例）的VM，未检测到TEK突变。热点突变c.1624G>A、c.1633G>A和c.3140A>G（p.Glu542Lys、p.Glu545Lys和p.His1047Arg）在PIK 3CA相关癌症、过度生长综合征和淋巴管畸形（LM）中常见，占携带突变个体的92%以上。与TEK中的VM致病突变一样，PIK 3CA突变在人脐静脉内皮细胞（HUVEC）中表达时引起AKT的慢性激活、某些重要血管生成因子的失调和异常内皮细胞形态。p110 α特异性抑制剂BYL 719恢复了PIK 3CA和TEK突变体HUVEC中测试的所有异常表型，表明它们通过相同的致病途径起作用。然而，在PIK 3CA与TEK突变的个体之间观察到病变定位和组织学的显著基因型-表型相关性，这表明基因特异性效应。
Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110 alpha subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations. Like VM-causative mutations in TEK, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in human umbilical vein endothelial cells (HUVECs). The p110 alpha-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific effects.