BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease

Maria Giulia Cangi, Riccardo Biavasco, Giulio Cavalli, Greta Grassini, Elena Dal-Cin, Corrado Campochiaro, Barbara Guglielmi, Alvise Berti, Vito Lampasona, Andreas Von Deimling, Maria Grazia Sabbadini, Marina Ferrarini, Claudio Doglioni, Lorenzo Dagna

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Abstract

Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAFV600E 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. BRAFV600E 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 BRAFV600E 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 BRAFV600E 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.

Original languageEnglish
Pages (from-to)1596-1602
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume74
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

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Erdheim-Chester Disease
Oncogenes
Mutation
Biopsy
Histiocytes
Blood
Histiocytosis
Polymerase Chain Reaction
Monocytes
Assays
Immunohistochemistry

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

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BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease. / Cangi, Maria Giulia; Biavasco, Riccardo; Cavalli, Giulio; Grassini, Greta; Dal-Cin, Elena; Campochiaro, Corrado; Guglielmi, Barbara; Berti, Alvise; Lampasona, Vito; Von Deimling, Andreas; Sabbadini, Maria Grazia; Ferrarini, Marina; Doglioni, Claudio; Dagna, Lorenzo.

In: Annals of the Rheumatic Diseases, Vol. 74, No. 8, 01.08.2015, p. 1596-1602.

Research output: Contribution to journalArticle

Cangi, MG, Biavasco, R, Cavalli, G, Grassini, G, Dal-Cin, E, Campochiaro, C, Guglielmi, B, Berti, A, Lampasona, V, Von Deimling, A, Sabbadini, MG, Ferrarini, M, Doglioni, C & Dagna, L 2015, 'BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease', Annals of the Rheumatic Diseases, vol. 74, no. 8, pp. 1596-1602. https://doi.org/10.1136/annrheumdis-2013-204924
Cangi, Maria Giulia ; Biavasco, Riccardo ; Cavalli, Giulio ; Grassini, Greta ; Dal-Cin, Elena ; Campochiaro, Corrado ; Guglielmi, Barbara ; Berti, Alvise ; Lampasona, Vito ; Von Deimling, Andreas ; Sabbadini, Maria Grazia ; Ferrarini, Marina ; Doglioni, Claudio ; Dagna, Lorenzo. / BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease. In: Annals of the Rheumatic Diseases. 2015 ; Vol. 74, No. 8. pp. 1596-1602.
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abstract = "Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAFV600E 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. BRAFV600E 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 BRAFV600E 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 BRAFV600E 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.",
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T1 - BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease

AU - Cangi, Maria Giulia

AU - Biavasco, Riccardo

AU - Cavalli, Giulio

AU - Grassini, Greta

AU - Dal-Cin, Elena

AU - Campochiaro, Corrado

AU - Guglielmi, Barbara

AU - Berti, Alvise

AU - Lampasona, Vito

AU - Von Deimling, Andreas

AU - Sabbadini, Maria Grazia

AU - Ferrarini, Marina

AU - Doglioni, Claudio

AU - Dagna, Lorenzo

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAFV600E 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. BRAFV600E 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 BRAFV600E 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 BRAFV600E 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.

AB - Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAFV600E 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. BRAFV600E 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 BRAFV600E 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 BRAFV600E 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.

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