Somatic activating BRAF variants cause isolated lymphatic malformations

Somatic activating variants in PIK3CA, the gene that encodes the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been previously detected in similar to 80% of lymphatic malformations (LMs).(1,2) We report the presence of somatic activating variants in BRAF in individuals with LMs that do not possess pathogenic PIK3CA variants. The BRAF substitution p.Val600Glu (c.1799T>A), one of the most common driver mutations in cancer, was detected in multiple individuals with LMs. Histology revealed abnormal lymphatic channels with immunopositivity for BRAF(V600E) 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-mitogen-activated protein kinase (MAPK) pathway.(3) In addition, this work highlights the importance of genetic diagnosis prior to initiating medical therapy as more studies examine therapeutics for individuals with vascular malformations.

Automated summary

Somatic activating variants in BRAF have been detected in lymphatic malformation patients without pathogenic PIK3CA variants, highlighting the complexity of low-flow lymphatic malformations and the importance of genetic diagnosis prior to therapy.