Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes
Open Access
- 9 February 2017
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 2 (3), e89473
- https://doi.org/10.1172/jci.insight.89473
Abstract
Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing. Fifteen patients (21%) carried the known BRAF V600E mutation, and 11 patients (15%) carried various mutations in MAP2K1, which we confirm induce constitutive activation of extracellular signal–regulated kinase (ERK) and were sensitive to inhibitors of mitogen-activated protein kinase kinase (MEK, the product of MAP2K1). We also identified recurring ALK rearrangements, and 4 LCH patients with an uncommon in-frame deletion in BRAF (N486_P490del or N486_T491>K), resulting in constitutive activation of ERK with resistance to V600E-specific inhibitors. We subsequently describe clinical cases where patients with aggressive multisystem LCH experience dramatic and sustained responses to monotherapy with either dabrafenib or trametinib. These findings support our conclusion that comprehensive genomic profiling should be regularly applied to these disorders at diagnosis, and can positively impact clinical care.This publication has 40 references indexed in Scilit:
- Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA SequenceThe New England Journal of Medicine, 2014
- Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesisBlood, 2014
- Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester diseaseBlood, 2014
- BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groupsThe Journal of Experimental Medicine, 2014
- MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK InhibitionCancer Discovery, 2014
- Recurrent BRAF mutations in Langerhans cell histiocytosisBlood, 2010
- Bone Marrow Findings at Diagnosis in Patients with Multisystem Langerhans Cell HistiocytosisPediatric and Developmental Pathology, 2010
- Endocrine involvement in pediatric-onset langerhans' cell histiocytosis: a population-based studyThe Journal of Pediatrics, 2004
- Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell histiocytosisMedical and Pediatric Oncology, 2002
- Transformation of Mammalian Cells by Constitutively Active MAP Kinase KinaseScience, 1994