Somatic activating BRAF variants cause isolated lymphatic malformations

Abstract

Somatic activating variants in PIK3CA, the gene that encodes the p110 catalytic subunit of PI3K, have been previously detected in [~]80% of lymphatic malformations (LM).1; 2 We report the presence of somatic activating variants in BRAF in individuals with PIK3CA-negative LM. The BRAF substitution p.Val600Glu (c.1799T>A), one of the most common driver mutations in cancer, was detected in multiple individuals with LM. Histology revealed abnormal lymphatic channels with immunopositivity for BRAFV600E in endothelial cells that was otherwise indistinguishable from PIK3CA positive LM. The finding that BRAF variants contribute to low-flow LMs increases the complexity of prior models associating low flow vascular malformations (LM and venous malformations) with mutations in the PI3K-AKT-MTOR and high flow vascular malformations (arteriovenous malformations) with mutations in the RAS-MAPK pathway.3 Additionally, this work highlights the importance of genetic diagnosis prior to initiating medical therapy as more studies examine therapeutics for individuals with vascular malformations.