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.
BRAFV600E mutations were observed in 50% and 38% of the pulmonary and nonpulmonary LCH lesions, respectively. 40% of pulmonary LCH lesions harboured NRASQ61K/R mutations, whereas no NRAS mutations were identified in nonpulmonary LCH biopsies or in lung tissue control. In seven out of 11 NRASQ61K/R-mutated pulmonary LCH lesions, BRAFV600E 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. NRASQ61K/R mutations activated both the MAPK and AKT (protein kinase B) pathways. In the univariate analysis, the presence of concurrent BRAFV600E and NRASQ61K/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.
Abstract
Pulmonary Langerhans cell histiocytosis genetic landscape includes recurrent activating NRAS Q61 mutations http://ow.ly/YgsSm
Footnotes
Editorial comment in Eur Respir J 2016; 47: 1629–1631.
This article has supplementary material available from erj.ersjournals.com
Support statement: The authors acknowledge support from Legs Poix (Chancellerie des Universités) and the Fonds de Dotation Recherche en Santé Respiratoire. Funding information for this article has been deposited with FundRef.
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
- Received October 9, 2015.
- Accepted February 11, 2016.
- Copyright ©ERS 2016