Whole Exome Sequencing of DNA from Langerhans Cell Histiocytosis Lesions. Homo sapiens

Langerhans cell histiocytosis (LCH) is characterized by the inappropriate accumulation of cells that share phenotypic characteristics with Langerhans cells, the primary antigen-presenting cells of skin and mucosa. The disease has a broad spectrum of clinical behaviors, from a mild self-limited version to an aggressive form associated with a 20% mortality. Treatment has generally been empiric. Mild disease responds to intralesional steroids or systemic therapy with vinblastine plus steroids. Combination anti-neoplastic therapies have been used with some success against more aggressive forms but they are associated with substantial toxicity and some patients are refractory. The discovery of somatic activating BRAF mutations – in particular, but not exclusively, BRAF V600E – in 50-60% of patients with LCH has brought the promise of targeted therapeutics to these patients. A recent report describes clinical responses to vemurafenib, a BRAF inhibitor, in patients with a mixture of LCH and Erdheim-Chester disease,8 another disorder associated with BRAF V600E,9 suggesting that BRAF V600E is a driver mutation in LCH. However, the ERK signaling pathway is activated in pathologic histiocytes of all LCH patients including those with wild type BRAF alleles. In order to discover other genetically driven mechanisms for activating ERK signaling in LCH, we performed whole exome sequencing on DNA from lesional and normal cells from three LCH patients.