Somatic PIK3CA mutations as a driver of sporadic venous malformations

Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyenet al, 2014; Uebelhoeret al, 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification ofTEKmutations in a proportion of VM (Limayeet al, 2009). We report that activatingPIK3CAmutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations inPIK3CAand related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lackTEKalterations.PIK3CAmutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.