V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare disease presenting with usually a localized disease but sometimes a widespread aggressive disorder especially in children. Among the somatic mutations in RAF-MEK-ERK pathway, especially mutation has been detected so far in LCH. We aimed in this study to investigate the prognostic significance of the mutations of target genes playing a role in the RAF-MEK-ERK pathway in pediatric LCH. Mutation analyses were performed on tumor DNA extracted from formalin-fixed paraffin-embedded biopsy specimens of 38 pediatric LCH cases using a direct sequencing technique for , , , and genes. The mutational status was correlated statistically with survival, clinical progression (disease relapse), and the established clinical prognostic parameters of LCH such as age, gender, localization, multisystem disease, central nervous system risk lesions, and risk organ or special-site involvement. V600E mutation was detected in 14 cases (36.8%), whereas mutation was found in only 1 case. No mutations were identified for and genes. The association of V600E mutation was significant in children with multisystem disease, younger age (<2 years), skin, and special organ involvement. V600E mutation was an independent predictive parameter for disease relapse. We therefore conclude that V600E mutation may be a significant marker for predicting disease progression in LCH and a candidate for targeted therapy for children with disease relapse and multisystem disease.