Molecular Profiling of Tumor Tissue and Plasma Cell-Free DNA from Patients with Non-Langerhans Cell Histiocytosis

The mutation and BRAF inhibitor responsiveness characterize ∼50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, = 35; Rosai-Dorfman disease (RDD), = 3; mixed ECD/RDD, = 1] using PCR and/or next-generation sequencing [tissue and cell-free DNA (cfDNA) of plasma and/or urine]. Of 34 evaluable patients, 17 (50%) had the mutation. Of 31 patients evaluable for non- alterations, 18 (58%) had ≥1 alteration and 12 putative non- MAPK pathway alterations: atypical mutation; , and mutations; or amplifications; (TRK inhibitor-sensitive) and fusions. Four patients had alterations, which can correlate with myeloid neoplasms, a known ECD predisposition, and one developed myelofibrosis 13 months after cfDNA testing. Therefore, our multimodal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH.