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.

• Authors: Filip Janku, Eli L Diamond, Aaron M Goodman, Vaijayanthi Kandadai Raghavan, Tamara G Barnes, Shumei Kato, Omar Abdel-Wahab, Benjamin H Durham, Funda Meric-Bernstam, Razelle Kurzrock
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 6 Pg. 1149-1157 (06 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 31015311 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Cell-Free Nucleic Acids
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinases

Topics

• Adolescent
• Adult
• Aged
• Cell-Free Nucleic Acids (genetics)
• Early Detection of Cancer (methods)
• Erdheim-Chester Disease (blood, pathology, urine)
• Female
• Genomics (methods)
• High-Throughput Nucleotide Sequencing
• Histiocytosis, Sinus (blood, pathology, urine)
• Humans
• Leukemia, Myeloid (diagnosis)
• Male
• Middle Aged
• Mitogen-Activated Protein Kinases (genetics)
• Mutation
• Polymerase Chain Reaction
• Proto-Oncogene Proteins B-raf (genetics)
• Young Adult