Sporadic venous malformation is caused by somatic mutations in TIE2

Venous malformations (VM) are the most frequent vascular malformations referred to vascular anomaly centers. An autosomal dominant familial form, termed cutaneomucosal venous malformation (VMCM), representing about 1% of venous lesions, is caused by gain-of-function mutations in the TIE2 gene. The aetiology of sporadic VM, which represents more than 95% of venous lesions, has however remained unknown. Here we show that sporadic VMs are caused by somatic mutations in TIE2. We identified seven missense mutations in VM tissue-derived DNA, which were however absent in blood DNA from these patients, and in tissue DNA from 90 controls. All of the mutations, predicted by bioinformatic analysis to have deleterious effects of varying severity on protein function, were found to result in a strong in vitro ligand-independent increase in phosphorylation of TIE2. In some patients, we observed two mutations acting in cis. Such combinations on the same allele induced even higher phosphorylation levels of the receptor than the constituent single mutations. Additional mutations were identified in lesion-derived cDNA, suggesting that the number of cells carrying a mutation can be in the minority, making the reduction of tissue heterogeneity an important factor in mutation detection. These data provide molecular evidence that sporadic venous malformations are caused by somatic activating TIE2 mutations, which are often linked to additional somatic genetic events. They explain the localized, predominantly unifocal nature of these lesions, and furthermore, pinpoint the TIE2 signaling pathway as a target for the development of therapeutic interventions. (miikka.vikkula@uclouvain.be)