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Genetic landscape of adult Langerhans cell histiocytosis with lung involvement

Authors :
Emmanuelle Clappier
Sylvie Chevret
Abdellatif Tazi
Alexandre How-Kit
Véronique Meignin
Emmanuelle Bugnet
Caroline Kannengiesser
Gwenaël Lorillon
Samia Mourah
Alain Haziot
Céleste Lebbé
Fanélie Jouenne
Aurélie Sadoux
Dominique Gossot
Shannon Cohen
Source :
European Respiratory Journal. 55:1901190
Publication Year :
2019
Publisher :
European Respiratory Society (ERS), 2019.

Abstract

The clinical significance of the BRAFV600E mutation in adult Langerhans cell histiocytosis (LCH), including pulmonary Langerhans cell histiocytosis (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 patients, 83 with PLCH (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 sequencing (WES) or targeted gene panel next-generation sequencing (NGS). Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression.MAPK pathway alterations were detected in 59 out of 69 cases (86%) (BRAFV600E mutation: 36%, BRAFN486_P490 deletion: 28%, MAP2K1 mutations: 15%, 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 reports 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.

Details

ISSN :
13993003 and 09031936
Volume :
55
Database :
OpenAIRE
Journal :
European Respiratory Journal
Accession number :
edsair.doi.dedup.....bd8d71fca3732aba188217ba53780cb7
Full Text :
https://doi.org/10.1183/13993003.01190-2019