title: BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease.
abstract: OBJECTIVE
  Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAF(V600E) mutation has been reported in biopsies in 19 out of 37 patients with ECD from the largest published cohort, but never found in the patients' peripheral blood. Also, the role of the mutation in the pathogenesis of the disease has not been elucidated yet. BRAF(V600E) has been associated with oncogene-induced senescence (OIS), a protective mechanism against oncogenic events, characterised by the induction of proinflammatory pathways.
  
  
  METHODS
  We verified the BRAF status in biopsies and peripheral blood from 18 patients with ECD from our cohort and matched controls by means of immunohistochemistry and of an ultrasensitive assay, based on the combination of a locked nucleic acid PCR and pyrosequencing. Droplet digital PCR was used to confirm the findings. We also evaluated the presence of senescence markers in ECD histiocytes.
  
  
  RESULTS
  BRAF(V600E) mutation was present in all the biopsy and peripheral blood samples from patients with ECD and in none of the controls. ECD histiocytes and a fraction of circulating monocytes from patients with ECD showed signs of a constitutive activation of the MAPK pathway. Moreover, BRAF-mutated histiocytes expressed markers of OIS.
  
  
  CONCLUSIONS
  The oncogenic BRAF(V600E) mutation is present in biopsies and in the peripheral blood from all patients with ECD who were evaluated and is associated with OIS. These findings have significant implications for the pathogenesis, diagnosis and treatment of ECD.
authors.affiliation: Unit of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Cangi
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Biavasco
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cavalli
authors.affiliation: Unit of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Greta
authors.initials: G
authors.lastname: Grassini
authors.affiliation: Unit of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Dal-Cin
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Campochiaro
authors.affiliation: Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Guglielmi
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alvise
authors.initials: A
authors.lastname: Berti
authors.affiliation: Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Lampasona
authors.affiliation: Department of Neuropathology, Heidelberg University, and CCU Neuropathology, DKFZ, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Sabbadini
authors.affiliation: Unit of Biology of Myeloma, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ferrarini
authors.affiliation: Unit of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Dagna
mesh_terms: D000328:Adult; D000368:Aged; D016922:Cellular Senescence / Q000235:genetics*; D031249:Erdheim-Chester Disease / Q000235:genetics*; D005260:Female; D006644:Histiocytes / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009857:Oncogenes / Q000502:physiology; D016133:Polymerase Chain Reaction / Q000379:methods; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D017421:Sequence Analysis
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Cytokines; Gene Polymorphism; Inflammation