Mosaicism of BRAF(V600E) in Healthy Skin Predicts Neurodegeneration in Histiocytosis

Most histiocytoses harbor an oncogenic somatic alteration activating the MAP kinase pathway, the most frequent of which is BRAF ^V600E . Targeted therapy with BRAF or MEK inhibitors is highly effective, but neurodegeneration remains a severe complication. Recent data suggest that neurodegeneration may be secondary to mosaicism for BRAF ^V600E in microglia. In the prospective observational TARGET-HISTIO cohort study, we investigated extra-CNS mosaicism of BRAF ^V600E in a cohort of 124 adults with histiocytosis. Seeking widespread mosaicism, we analyzed healthy skin biopsies from areas without histiocytosis or melanocytic infiltration using high-sensitivity digital polymerase chain reaction. BRAF ^V600E was detected in healthy skin in 57/67 (85%) patients with BRAF ^V600E histiocytosis and was present in all second and third skin biopsies (n=6). BRAF ^V600E was absent from skin biopsies in all 37 patients with histiocytosis harboring another oncogenic mutation. BRAF ^V600E was also present in skin biopsies of four /20 patients with histiocytosis of unknown molecular status. Cells harboring BRAF ^V600E share characteristics with resident dermis macrophages. Only 58% of patients with BRAF ^V600E in skin also had BRAF ^V600E in blood leukocytes. Variant allele frequency in skin and blood leukocytes was 16 times lower than in histiocytosis, and frequency in skin was independent of treatment with BRAF/MEK inhibitors. None of the patients with wild type BRAF alleles in skin had neurodegeneration, whereas 22/61 (36%) of patients with BRAF ^V600E in skin had neurodegeneration. This study demonstrates that mosaicism of BRAF ^V600E in healthy skin is frequent in patients with histiocytosis and is strongly associated with neurodegeneration.