Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders.

TitleBiological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders.
Publication TypeJournal Article
Year of Publication2015
AuthorsAllen, CE, D Parsons, W
JournalHematology Am Soc Hematol Educ Program
Volume2015
Pagination559-64
Date Published2015
ISSN1520-4383
KeywordsCell Differentiation, Clinical Trials as Topic, Enzyme Activation, Erdheim-Chester Disease, Exome, Genome, Human, Genotype, GTP Phosphohydrolases, Histiocytosis, Langerhans-Cell, Humans, MAP Kinase Kinase 1, MAP Kinase Signaling System, Membrane Proteins, Mutation, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins B-raf, Sequence Analysis, DNA, Xanthogranuloma, Juvenile
Abstract

Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Erdheim-Chester disease (ECD) represent histiocytic disorders with a wide range of clinical manifestations. Until recently, mechanisms of pathogenesis have been speculative and debate has focused on classification of these conditions as reactive versus neoplastic. Genomic studies have been challenged by scarce tissue specimens, as well as heterogeneous nature of the lesions with variable infiltration of pathologic histiocytes. Whole-exome sequencing recently revealed a very low frequency of somatic mutations in LCH, JXG, and ECD compared to other neoplastic disorders. However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD. In ECD, recurrent mutations in the PI3K pathway gene PIK3CA have also been described. The heterogeneous clinical manifestations of these disorders may therefore be the cumulative result of activation of MAPK mutations (along with modifying signals from other pathways) at distinct stages of myeloid differentiation. Implications of this model include redefinition of LCH, JXG, and ECD as a group of clinically diverse myeloid neoplastic disorders with a common mechanism of pathogenesis. This model supports refocusing therapeutic strategies for these diseases on a personalized approach based on specific mutations and the cell(s) of origin.

DOI10.1182/asheducation-2015.1.559
Alternate JournalHematology Am Soc Hematol Educ Program
PubMed ID26637772