RecurrentNRASmutations in pulmonary Langerhans cell histiocytosis
| Autor: | Jörg Tost, Gwenaël Lorillon, Céleste Lebbé, Véronique Meignin, Sylvie Chevret, Abdellatif Tazi, Alexandre How-Kit, Florence Mauger, Samia Mourah, Dominique Gossot, Emmanuelle Bugnet |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Adult
Male Proto-Oncogene Proteins B-raf 0301 basic medicine Pulmonary and Respiratory Medicine Neuroblastoma RAS viral oncogene homolog Pathology medicine.medical_specialty Genotype MAP Kinase Signaling System Biopsy MAP Kinase Kinase 1 Context (language use) medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Langerhans cell histiocytosis MAP2K1 medicine Humans Lung Mutation business.industry Smoking Sequence Analysis DNA medicine.disease Histiocytosis Langerhans-Cell Histiocytosis Treatment Outcome 030104 developmental biology 030220 oncology & carcinogenesis Disease Progression ras Proteins Cancer research Female KRAS business V600E |
| Zdroj: | European Respiratory Journal. 47:1785-1796 |
| ISSN: | 1399-3003 0903-1936 |
| Popis: | The mitogen-activated protein kinase (MAPK) pathway is constantly activated in Langerhans cell histiocytosis (LCH). Mutations of the downstream kinasesBRAFandMAP2K1mediate this activation in a subset of LCH lesions. In this study, we attempted to identify other mutations which may explain the MAPK activation in nonmutatedBRAFandMAP2K1LCH lesions.We analysed 26 pulmonary and 37 nonpulmonary LCH lesions for the presence ofBRAF,MAP2K1,NRASandKRASmutations. Grossly normal lung tissue from 10 smoker patients was used as control. Patient spontaneous outcomes were concurrently assessed.BRAFV600Emutations were observed in 50% and 38% of the pulmonary and nonpulmonary LCH lesions, respectively. 40% of pulmonary LCH lesions harbouredNRASQ61K/Rmutations, whereas noNRASmutations were identified in nonpulmonary LCH biopsies or in lung tissue control. In seven out of 11NRASQ61K/R-mutated pulmonary LCH lesions,BRAFV600Emutations were also present. Separately genotyping each CD1a-positive area from the same pulmonary LCH lesion demonstrated that these concurrentBRAFandNRASmutations were carried by different cell clones.NRASQ61K/Rmutations activated both the MAPK and AKT (protein kinase B) pathways. In the univariate analysis, the presence of concurrentBRAFV600EandNRASQ61K/Rmutations was significantly associated with patient outcome.These findings highlight the importance ofNRASgenotyping 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|