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

摘要

The BRAF(V600E) mutation and BRAF inhibitor responsiveness characterize similar to 50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, n = 35; Rosai-Dorfman disease (RDD), n = 3; mixed ECD/RDD, n = 1] using BRAF(V600E )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 BRAF(V600E) mutation. Of 31 patients evaluable for non-BRAF(V600E) alterations, 18 (58%) had >= 1 alteration and 12 putative non-BRAF(V600E) MAPK pathway alterations: atypical BRAF mutation; GNAS, MAP2K1, MAP2K2, NF1 and RAS mutations; RAF1 or ERBB2 amplifications; LMNA-NTRK1 (TRK inhibitor-sensitive) and CAPZA2-BRAF fusions, Four patients had JAK2, MPL, ASXL1, U2AF1 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.