title: Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes.
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 knownBRAFV600E mutation, and 11 patients (15%) carried various mutations inMAP2K1, 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 ofMAP2K1). We also identified recurringALKrearrangements, and 4 LCH patients with an uncommon in-frame deletion inBRAF(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.
authors.affiliation: Cancer and Blood Diseases Institute, Division of Oncology, Cincinnati Children's Hospital Medical Center.
authors.forename: Lynn H
authors.initials: LH
authors.lastname: Lee
authors.affiliation: Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center.
authors.forename: Anjelika
authors.initials: A
authors.lastname: Gasilina
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center.
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Roychoudhury
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center.
authors.forename: Jason
authors.initials: J
authors.lastname: Clark
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
authors.affiliation: Cancer and Blood Diseases Institute, Division of Oncology, Cincinnati Children's Hospital Medical Center.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pressey
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Grimley
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lorsbach
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Siraj
authors.initials: S
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Bailey
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center.
authors.forename: Nicolas N
authors.initials: NN
authors.lastname: Nassar
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center.
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Kumar
mesh_terms: D016475:3T3 Cells; D000328:Adult; D000077548:Anaplastic Lymphoma Kinase / Q000235:genetics*; D000818:Animals; D019008:Drug Resistance, Neoplasm; D005260:Female; D015614:Histiocytosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D007223:Infant; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage / Q000627:therapeutic use; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage / Q000627:therapeutic use; D011744:Pyrimidinones / Q000008:administration & dosage / Q000627:therapeutic use; D017422:Sequence Analysis, DNA / Q000379:methods*; D017423:Sequence Analysis, RNA / Q000379:methods*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C561627:dabrafenib