Somatic Activating PIK3CA Mutations Cause Venous Malformation

• Published in: American journal of human genetics 2015-12, Vol.97 (6), p.914-921
• Main Authors: Limaye, Nisha, Kangas, Jaakko, Mendola, Antonella, Godfraind, Catherine, Schlögel, Matthieu J., Helaers, Raphael, Eklund, Lauri, Boon, Laurence M., Vikkula, Miikka
• Format: Article
• Language: English
• Subjects: Alleles; Cancer; Cells; Class I Phosphatidylinositol 3-Kinases; Gene Expression Regulation; Gene Frequency; Genetic Association Studies; Genotype & phenotype; High-Throughput Nucleotide Sequencing; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - enzymology; Human Umbilical Vein Endothelial Cells - pathology; Humans; Kinases; Morphology; Mutation; Neovascularization, Pathologic - enzymology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Receptor, TIE-2 - antagonists & inhibitors; Receptor, TIE-2 - genetics; Receptor, TIE-2 - metabolism; Signal Transduction; Thiazoles - pharmacology; Transfection; Vascular Malformations - enzymology; Vascular Malformations - genetics; Vascular Malformations - pathology; Veins - enzymology; Veins - pathology
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2015.11.011

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 p110α 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 p110α-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.