Abstract
The clinical significance of the BRAFV600E mutation in adult Langerhans cell histiocytosis (LCH), including pulmonary LCH (PLCH), is not well understood. Similarly, the spectrum of molecular alterations involved in adult LCH has not been fully delineated. To address these issues, we genotyped a large number of adult LCH biopsies and searched for an association of identified molecular alterations with clinical presentation and disease outcome.
Biopsies from 117 adult LCH (83 PLCH) patients (median age 36.4 years, 56 females, 38 multisystem disease, 79 single system disease, 65 current smokers) were genotyped for the BRAFV600E mutation. In 69 cases, LCH lesions were also genotyped by whole-exome or targeted gene panel next-generation sequencing. Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression.
MAPK pathway alterations were detected in 59 (86%) cases: BRAFV600E mutation (36%), BRAFN486_P490 deletion (28%), MAP2K1 mutations (15%), and isolated NRASQ61 mutations (4%), while KRAS mutations were virtually absent in PLCH lesions. The BRAFV600E mutation was not associated with LCH presentation at diagnosis, including smoking status and lung function, in PLCH patients. BRAFV600E status did not influence the risk of LCH progression over time.
Thus, MAPK alterations are present in most lesions from adult LCH patients, particularly in PLCH. Unlike what was reported in paediatric LCH, BRAFV600E genotyping did not provide additional information on disease outcome. The search for alterations involved in the MAPK pathway, including BRAF deletions, is useful for guiding targeted treatment in selected patients with refractory progressive LCH.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. JOUENNE has nothing to disclose.
Conflict of interest: Dr. chevret has nothing to disclose.
Conflict of interest: Dr. Bugnet has nothing to disclose.
Conflict of interest: Dr. CLAPPIER has nothing to disclose.
Conflict of interest: Dr. Lorillon reports other from VITALAIRE, other from CHIESI, outside the submitted work.
Conflict of interest: Dr. Meignin has nothing to disclose.
Conflict of interest: Dr. SADOUX has nothing to disclose.
Conflict of interest: Dr. Cohen has nothing to disclose.
Conflict of interest: Dr. Haziot has nothing to disclose.
Conflict of interest: Dr. How-Kit has nothing to disclose.
Conflict of interest: Dr. KANNENGIESSER has nothing to disclose.
Conflict of interest: Dr. Lebbe reports personal fees from Amgen, grants and personal fees from BMS, grants and personal fees from MSD, grants and personal fees from Roche, grants and personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Sanofi, personal fees from Merck serono, personal fees from Pfizer, personal fees from Incyte, outside the submitted work.
Conflict of interest: Dr. Gossot reports personal fees from Delacroix-Chevalier (Instrument manufacturer), outside the submitted work.
Conflict of interest: Dr. Mourah reports other from Novartis, other from Roche, outside the submitted work.
Conflict of interest: Dr. Tazi reports personal fees from Bristol-Myers Squibb, other from Boehringer Ingelheim, other from Teva, other from Vitalaire, other from Astrazeneca, outside the submitted work.
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- Received June 17, 2019.
- Accepted November 13, 2019.
- Copyright ©ERS 2019