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

Abstract

The BRAF V600E 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, 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.

Conflict of interest statement

Conflict of Interest: Filip Janku has research support from Novartis, Genentech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, FujiFilm Corporation and Upsher-Smith Laboratories; is on the Scientific Advisory Boards of IFM Therapeutics, Synlogic, Guardant Health and Deciphera; is a paid consultant for Trovagene and Immunomet; and has ownership interests in Trovagene. Dr. Razelle Kurzrock receives research funding from Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant; consultant fees from Sequenom, LOXO, Actuate Therapeutics, and Genentech; and speaker fees from Roche. Dr. Kurzrock also has an ownership interest in CureMatch, Inc.

©2019 American Association for Cancer Research.

Figures

Figure 1

Of 39 patients with Erdheim-Chester disease (ECD, n=35), Rosai-Dorfman disease (RDD, n=3) and mixed ECD/RDD (n=1) the valid results from at least on method of molecular testing were available for 34 patients. The diagram depicts the distribution and overlap of the testing methods used such as tumor tissue targeted next-generation sequencing (NGS), tumor tissue PCR for the BRAFV600E mutation, plasma-derived cell-free (cf) DNA targeted NGS and urine-derived cfDNA PCR for the BRAFV600E mutation.

Figure 2

Number of the genomic alterations detected by the targeted next-generation sequencing (NGS) of tumor tissue (A.) and plasma-derived cell-free (cf) DNA (C.). Distribution of the genomic alterations detected by the targeted NGS of tumor tissue (B.) and plasma-derived cfDNA (D.).