Mutually Exclusive Recurrent Somatic Mutations in MAP2K1 and BRAF Support a Central Role for ERK Activation in LCH Pathogenesis

Langerhans Cell Histiocytosis (LCH) is a myeloproliferative disorder characterized by lesions composed of pathologic CD207+ dendritic cells (DCs) with an inflammatory infiltrate. BRAFV600E remains the only recurrent mutation reported in LCH. In order to evaluate the spectrum of somatic mutations in LCH, whole exome sequencing (WES) was performed on matched LCH and normal tissue samples obtained from 41 patients. Lesions from other histiocytic disorders, juvenile xanthogranuloma (JXG), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD) were also evaluated. All of the lesions from histiocytic disorders were characterized by an extremely low overall rate of somatic mutations. Notably, 33% (7/21) of LCH cases with wild-type BRAF and none (0/20) with BRAFV600E harbored somatic mutations in MAP2K1 (six in-frame deletions and one missense mutation) that induced ERK phosphorylation in vitro. Single cases of somatic mutations of the MAPK pathway genes ARAF and ERBB3 were also detected. The ability of MAPK pathway inhibitors to suppress MEK and ERK phosphorylation in cell culture and primary tumor models was dependent on the specific LCH mutation. The findings of this study support a model in which ERK activation is a universal endpoint in LCH arising from pathologic activation of upstream signaling proteins.