title: Recurrent NRAS mutations in pulmonary Langerhans cell histiocytosis.
abstract: The mitogen-activated protein kinase (MAPK) pathway is constantly activated in Langerhans cell histiocytosis (LCH). Mutations of the downstream kinases BRAF and MAP2K1 mediate this activation in a subset of LCH lesions. In this study, we attempted to identify other mutations which may explain the MAPK activation in nonmutated BRAF and MAP2K1 LCH lesions.We analysed 26 pulmonary and 37 nonpulmonary LCH lesions for the presence of BRAF, MAP2K1, NRAS and KRAS mutations. Grossly normal lung tissue from 10 smoker patients was used as control. Patient spontaneous outcomes were concurrently assessed.BRAF(V600E) mutations were observed in 50% and 38% of the pulmonary and nonpulmonary LCH lesions, respectively. 40% of pulmonary LCH lesions harboured NRAS(Q61K) (/R) mutations, whereas no NRAS mutations were identified in nonpulmonary LCH biopsies or in lung tissue control. In seven out of 11 NRAS(Q61K) (/R)-mutated pulmonary LCH lesions, BRAF(V600) (E) mutations were also present. Separately genotyping each CD1a-positive area from the same pulmonary LCH lesion demonstrated that these concurrent BRAF and NRAS mutations were carried by different cell clones. NRAS(Q61K) (/R) mutations activated both the MAPK and AKT (protein kinase B) pathways. In the univariate analysis, the presence of concurrent BRAF(V600E) and NRAS(Q61K) (/R) mutations was significantly associated with patient outcome.These findings highlight the importance of NRAS genotyping of pulmonary LCH lesions because the use of BRAF inhibitors in this context may lead to paradoxical disease progression. These patients might benefit from MAPK kinase inhibitor-based treatments.
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Laboratoire de Pharmacologie Biologique, Hôpital Saint-Louis; Université Paris-Diderot, Sorbonne Paris Cité; INSERM U976, Paris, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
authors.affiliation: Laboratoire de Génomique fonctionnelle, Fondation Jean Dausset - CEPH, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: How-Kit
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Service de Pathologie, Hôpital Saint-Louis; INSERM UMR_S1165, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Meignin
authors.affiliation: Département Thoracique, Institut Mutualiste Montsouris, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Gossot
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Centre National de Référence de l'Histiocytose Langerhansienne, Service de Pneumologie, Hôpital Saint-Louis, Paris, France.
authors.forename: Gwenaël
authors.initials: G
authors.lastname: Lorillon
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Centre National de Référence de l'Histiocytose Langerhansienne, Service de Pneumologie, Hôpital Saint-Louis, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bugnet
authors.affiliation: Laboratoire Epigénétique et Environnement, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Mauger
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Département de Dermatologie, Hôpital Saint-Louis; Université Paris-Diderot, Sorbonne Paris Cité; INSERM U976, Paris, France.
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbe
authors.affiliation: Assistance Publique - Hôpitaux de Paris; Service de Biostatistique et Information Médicale, Hôpital Saint-Louis, Paris, France Université Paris-Diderot, Sorbonne Paris Cité; INSERM UMR 1153 CRESS, Equipe de Recherche en Biostatistiques et Epidémiologie Clinique, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.affiliation: Laboratoire Epigénétique et Environnement, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France.
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Centre National de Référence de l'Histiocytose Langerhansienne, Service de Pneumologie, Hôpital Saint-Louis, Paris, France Université Paris-Diderot, Sorbonne Paris Cité; INSERM UMR 1153 CRESS, Equipe de Recherche en Biostatistiques et Epidémiologie Clinique, Paris, France abdellatif.tazi@sls.aphp.fr.
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Tazi
mesh_terms: D000328:Adult; D001706:Biopsy; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006646:Histiocytosis, Langerhans-Cell / Q000235:genetics*; D006801:Humans; D008168:Lung / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D020935:MAP Kinase Signaling System; D008297:Male; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012907:Smoking; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D018631:ras Proteins