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Genetic Alterations in Adult Pulmonary Langerhans Cell Histiocytosis

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A2299 - Genetic Alterations in Adult Pulmonary Langerhans Cell Histiocytosis
Author Block: A. Tazi1, F. Jouenne2, C. Laurent-Issartel2, A. Sadoux2, G. Lorillon3, V. Meignin4, C. Leschi2, E. Bugnet3, S. Mourah2; 1Centre National de Référence des Histiocytoses, Service de Pneumologie, AP-HP, Hôpital Saint-Louis; Université Paris Diderot Sorbonne Paris Cité; U1153 CRESS, Equipe de Recherche en Biostatistiques et Epidémiologie Clinique, Paris, France, 2Laboratoire de Pharmacologie Biologique, AP-HP, Hôpital Saint-Louis, Université Paris Diderot, Sorbonne Paris Cité; INSERM U976, Paris, France, 3Centre National de Référence des Histiocytoses, Service de Pneumologie, AP-HP, Hôpital Saint-Louis, Paris, France, 4Service de Pathologie, AP-HP, Hôpital Saint-Louis; INSERM UMR_S1165, Paris, France.
Rationale: Alterations in the mitogen-activated protein kinase (MAPK) pathway are the main genomic abnormalities observed in Langerhans cell histiocytosis (LCH), including pulmonary LCH (PLCH). Apart from BRAF V600E mutation and MAP2K1 alterations, other genomic abnormalities have been reported in non PLCH lesions, which in some cases may coexist in the same tissue specimen. We also previously described a significant proportion of recurrent subclonal NRASQ61 mutations in adult PLCH, frequently associated with BRAFV600E mutation, at a low allele frequency. Importantly, MAPK pathway was shown to be activated in virtually all LCH lesions (including PLCH), even in the absence of mutations, suggesting that additional mechanisms are involved. Methods: Here, we widely genotyped 59 surgical lung lesions from 56 PLCH patients (median age 36 years, 30 females, 53 smokers, 46 isolated PLCH), using a custom-designed next-generation sequencing (NGS) panel of 79 genes including genes of the MAPK pathway, Enhanced-Ice-Cold PCR and Sanger sequencing. Results: Genotyping data analysis was informative for 57 lesions of which 79% harbored at least one genomic alteration. Forty six percent (26/57) were BRAF V600E mutated, and 3 cases harbored other BRAF mutations, i.e. BRAFG469A, L584F and R603X. We also looked for the recently described BRAF deletions in LCH lesions, which we identified in 4/24 (17%) tested specimens. RAS mutations (NRASQ61, G60E, G12D and KRAS G12S and G13S) were identified in 16/57 (28%) lesions. MAP2K1 gene alterations were observed in 11/45 (24%) tested specimens, including E102_I103 deletion and hotspot mutations (R47Q, Q56P, R108W and C121S). In some cases, these different genomic alterations of the MAPK pathway were subclonal and concurrently present in the same lung specimen. Additionally, 4 PLCH lesions harbored several non-MAPK genetic variants, including DUSP4, ERBB2, ERBB4, NOTCH1 and MET mutations, which were predicted to have potential pathogenic consequences. These mutations were constantly associated with a MAPK gene alteration in the same lesion. Conclusions: Variable MAPK pathway gene alterations were present in adult PLCH biopsies, as well as new candidate genes, which illustrate the complex genetic landscape of PLCH lesions potentially involved in the pathogenesis of this rare disease. Because of the variable sensitivity to MAPK inhibitors of the different gene(s) alteration(s) identified in PLCH lesions (such as BRAFV600E mutation vs. BRAF deletion), our results stress the importance of a wide genomic evaluation of PLCH lesions to best guide the choice of MAPK targeted treatments that could be used in patients with refractory progressive disease.
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