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

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.

[1]  Soyoung Lee,et al.  Synthetic lethal metabolic targeting of cellular senescence in cancer therapy , 2013, Nature.

[2]  L. Borsu,et al.  Detection of an NRAS mutation in Erdheim-Chester disease. , 2013, Blood.

[3]  Kelly J. Morris,et al.  A complex secretory program orchestrated by the inflammasome controls paracrine senescence , 2013, Nature Cell Biology.

[4]  Yuri E Nikiforov,et al.  Pulmonary Langerhans cell histiocytosis: profiling of multifocal tumors using next-generation sequencing identifies concordant occurrence of BRAF V600E mutations. , 2013, Chest.

[5]  P. Cluzel,et al.  Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. , 2013, Blood.

[6]  S. Larson,et al.  Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. , 2013, The New England journal of medicine.

[7]  C. Campochiaro,et al.  The multifaceted clinical presentations and manifestations of Erdheim–Chester disease: comprehensive review of the literature and of 10 new cases , 2013, Annals of the rheumatic diseases.

[8]  L. Zender,et al.  T-helper-1-cell cytokines drive cancer into senescence , 2013, Nature.

[9]  Michael B Atkins,et al.  Which drug, and when, for patients with BRAF-mutant melanoma? , 2013, The Lancet. Oncology.

[10]  J. Emile,et al.  BRAF mutations in Erdheim-Chester disease. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  S. Lade,et al.  Erdheim-Chester disease harboring the BRAF V600E mutation. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  K. Flaherty,et al.  Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. , 2012, The New England journal of medicine.

[13]  C. Doglioni,et al.  Tumor necrosis factor α as a master regulator of inflammation in Erdheim-Chester disease: rationale for the treatment of patients with infliximab. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  M. Copin,et al.  High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. , 2012, Blood.

[15]  A. Stenzinger,et al.  BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. , 2012, Blood.

[16]  J. Utikal,et al.  Improved survival with MEK inhibition in BRAF-mutated melanoma. , 2012, The New England journal of medicine.

[17]  Dirk Schadendorf,et al.  Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group , 2012 .

[18]  L. Zender,et al.  Immune surveillance of senescent cells--biological significance in cancer- and non-cancer pathologies. , 2012, Carcinogenesis.

[19]  F. Fraternali,et al.  B-RAF Mutant Alleles Associated with Langerhans Cell Histiocytosis, a Granulomatous Pediatric Disease , 2012, PloS one.

[20]  L. Dagna,et al.  Erdheim-Chester disease: imaging-guided therapeutic approach. , 2011, Clinical nuclear medicine.

[21]  M. Vieth,et al.  Up and downregulation of p16Ink4a expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer , 2011, Modern Pathology.

[22]  S. Pileri,et al.  BRAF mutations in hairy-cell leukemia. , 2011, The New England journal of medicine.

[23]  H. Zentgraf,et al.  Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody , 2011, Acta Neuropathologica.

[24]  S. Pfister,et al.  Genetic Aberrations Leading to MAPK Pathway Activation Mediate Oncogene-Induced Senescence in Sporadic Pilocytic Astrocytomas , 2011, Clinical Cancer Research.

[25]  L. Arnaud,et al.  Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients. , 2011, Blood.

[26]  L. Arnaud,et al.  CNS involvement and treatment with interferon-α are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients. , 2011, Blood.

[27]  F. Galateau-Sallé,et al.  Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease. , 2010, Blood.

[28]  W. Hahn,et al.  Recurrent BRAF mutations in Langerhans cell histiocytosis. , 2010, Blood.

[29]  C. Wellbrock,et al.  BRAF as therapeutic target in melanoma. , 2010, Biochemical pharmacology.

[30]  M. Ferrarini,et al.  Erdheim-Chester disease: report on a case and new insights on its immunopathogenesis. , 2010, Rheumatology.

[31]  Misa Nakamura,et al.  Targeting of the BRAF gene in papillary thyroid carcinoma (review). , 2009, Oncology reports.

[32]  D. Peeper,et al.  Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network , 2008, Cell.

[33]  M. Kolodney,et al.  Selective amplification of rare mutations using locked nucleic acid oligonucleotides that competitively inhibit primer binding to wild-type DNA. , 2008, The Journal of investigative dermatology.

[34]  Carlos Cordon-Cardo,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2007, Nature.

[35]  Tu V. Huynh,et al.  Clonal cytogenetic abnormalities in Erdheim-Chester disease. , 2007, The American journal of surgical pathology.

[36]  M. Ferrarini,et al.  Immunohistochemical evidence of a cytokine and chemokine network in three patients with Erdheim-Chester disease: implications for pathogenesis. , 2006, Arthritis and rheumatism.

[37]  A. Kolbus,et al.  ERK and Beyond: Insights from B-Raf and Raf-1 Conditional Knockouts , 2006, Cell cycle.

[38]  J. Shay,et al.  BRAFE600-associated senescence-like cell cycle arrest of human naevi , 2005, Nature.

[39]  F. Sim,et al.  Erdheim-Chester disease. , 2003, Orthopedics.

[40]  L. Rimsza,et al.  Erdheim-Chester Disease: Case Report, PCR-Based Analysis of Clonality, and Review of Literature , 2002, Modern Pathology.

[41]  V. Paradis,et al.  Chester-Erdheim disease: a neoplastic disorder. , 1999, Human pathology.

[42]  C. Doglioni,et al.  TNF-α in Erdheim-Chester disease pericardial effusion promotes endothelial leakage in vitro and is neutralized by infliximab. , 2014, Rheumatology.

[43]  M. Ladanyi,et al.  Detection of KRAS and BRAF mutations in colorectal carcinoma roles for high-sensitivity locked nucleic acid-PCR sequencing and broad-spectrum mass spectrometry genotyping. , 2011, The Journal of molecular diagnostics : JMD.