Abstract

Background. Mitogen-activated protein kinase (MAPK) pathway is constantly activated in Langerhans cell histiocytosis (LCH), including pulmonary LCH (PLCH). Apart from BRAF^V600E mutation, other MAPK alterations (such as MAP2K1 mutations/deletions, NRAS mutations, BRAF deletions) have also been described in LCH, but have not been accurately evaluated in PLCH lesions.

Objective. To evaluate MAPK genetic alterations in PLCH lesions.

Methods. Surgical lung biopsies from 42 patients were genotyped (median age 36 years, 18 females, 41 smokers, 35 with single system disease), using custom-designed next-generation sequencing panel, Enhanced-Ice-Cold PCR, Sanger and pyrosequencing.

Results. The different molecular alterations observed are represented below.

A BRAF^V600E mutation and a N486_P490 BRAF deletion (shown to be resistant to BRAF inhibitors) were identified in the same specimen. One lesion harbored additional non-MAPK genetic variants, in DUSP4 and ERBB2 genes, predicted to have potential pathogenic consequences.

Conclusions. Variable MAPK pathway gene alterations were present in 37/42 (88%) PLCH lesions. Because of the variable sensitivity of the different gene(s) alteration(s) identified to MAPK targeting drugs, our results stress the importance of a wide genomic evaluation of PLCH lesions to best guide the choice of the most appropriate MAPK targeted treatment that could be used, as a salvage therapy, in the patients with refractory progressive disease.