Micro-mosaicism of <i>BRAF</i> V600E oncogene in normal skin samples of patients with Erdheim-Chester disease.

Abstract

e15073 Background: Erdheim-Chester disease (ECD) is a histiocyte neoplasm with frequent long bone, retroperitoneal, cardiovascular and/or central nervous system (CNS) involvements. More than half of ECD patients harbor a BRAF V600E mutation, and treatment with BRAF and/or MEK inhibitors is highly efficient in most patients. BRAF V600E is also frequent in Langerhans cell histiocytosis (LCH), which co-occurs in 14% of patients with ECD. Both ECD and LCH are associated with neurodegeneration (ND) predominating in cerebellum and pons. Detection of BRAF V600E was recently reported in microglia of brain samples of 8 patients with ECD or LCH, some of whom did not have ND (Vicario 2024). In mice, both microglia and epidermal Langerhans cells are self-renewed cells derived from yolk-sac progenitors. Methods: Patients with Erdheim-Chester with BRAF V600E mutation were included in this study. Normal skin samples were obtained either from biopsies in clinically healthy areas or from margin of basal cell carcinoma. Histology analysis of all samples excluded any histiocytosis or melanocytic tumor infiltration. Rolls were analyzed using digital PCR for wild type and V600E variants of BRAF as described (Hélias‐Rodzewicz 2023). Samples were considered as negative for BRAF V600E , when sequencing depth of BRAF was &gt; 10,000 (biopsies) or &gt; 20,000 (blood or bone marrow (BM) cells. Results: Twenty patients were included with median age 68 years (11males/9females). Nine patients were treated with BRAF and/or MEK inhibitors at time of skin biopsy. Eight patients had ND, and 5 had clonal hematopoiesis. BRAF V600E was detected in 18/20 patients. The variant allele frequency (VAF) was always &lt; 1% (median 0.16%, range 0.01% to 0.69%). Median VAF in normal skin was significantly lower than in histiocytosis infiltrated tissues (0.16% (IQR 0.06-0.19) vs 4.3% (IQR 2.9-13), p &lt; 0001). Two of the patients had 2 distinct skin biopsies, both positive for BRAF V600E . Blood and/or bone marrow cells were analyzed in 11 patients with BRAF V600E positive normal skin: 6 contained BRAF V600E , while 5 were wild type. ND was observed in 4/5 patients skin-positive and blood-negative for BRAF V600E , but in only 2/6 skin-positive and blood-negative for BRAF V600 . Conclusions: The oncogenic BRAF V600E variant is frequently present in normal skin of patients with ECD, even during treatment with BRAF/MEK inhibitors. The VAF is lower than in histiocytosis infiltrated biopsies. This suggest that these patients may have a micro-mosaicism of BRAF V600E within self-renewing epidermal Langerhans cells.