Somatic activating PIK3CA mutations cause sporadic venous malformation

Somatic mutations in the endothelial cell tyrosine kinase receptor TIE2/TEK cause more than half of sporadic unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110a subunit of PI3K, cause 54% (27 out of 50) of TIE2 mutation-negative VMs. The hotspot mutations E542K, E545K and H1047R, frequent in PIK3CA-associated cancers, overgrowth syndromes and lymphatic malformation (LM), account for >92% of mutation-positive patients. Like VM-causative mutations in TIE2, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in HUVECs. The p110?-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TIE2-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between patients with mutations in PIK3CA vs. TIE2, pointing to gene-specific effects.