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 language | English |
|---|---|
| Pages (from-to) | 1596-1602 |
| Number of pages | 7 |
| Journal | Annals of the Rheumatic Diseases |
| Volume | 74 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 1 2015 |
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ASJC Scopus subject areas
- Rheumatology
- Immunology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Allergy
Cite this
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 journal › Article
}
TY - JOUR
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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UR - http://www.scopus.com/inward/citedby.url?scp=84940385131&partnerID=8YFLogxK
U2 - 10.1136/annrheumdis-2013-204924
DO - 10.1136/annrheumdis-2013-204924
M3 - Article
C2 - 24671772
AN - SCOPUS:84940385131
VL - 74
SP - 1596
EP - 1602
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
SN - 0003-4967
IS - 8
ER -