Venous malformations: PIK3CA mutations guide new treatments

The Phosphoinositide 3-Kinase (PI3K) pathway has been extensively studied in tumors due its roles in promoting cellular growth and proliferation [1]. The most common PI3K mutations are in the PIK3CA gene encoding the p110α catalytic subunit, including the “hotspot” activating mutations E545K and H1047R that can lead to constitutive signaling of the pathway [1]. Consequently, activation of the serine/threonine kinase Akt can promote proliferative and cell growth pathways through regulation of mTOR and other intermediates [1]. In addition to driving tumorigenesis, hotspot PIK3CA mutations have also been shown to drive a wide spectrum of non-malignant over-growth disorders collectively termed the PIK3CA-Related Overgrowth Spectrum [2]. More recently, mutations in PIK3CA have been identified in venous malformations (VMs) [3], the most frequent form of vascular malformations with a frequency of about 1 in 5000 people in the general population [4]. These painful and often disfiguring lesions are characterized by endothelial cell overgrowth, loss of supporting mural cells, and a disorganized extracellular matrix resulting in dilated and distended vessels in a variety of tissues, with common occurrence in the cutaneous layer of the skin [4].