title: Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders.
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.
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX;
authors.forename: Carl E
authors.initials: CE
authors.lastname: Allen
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
authors.forename: D Williams
authors.initials: DW
authors.lastname: Parsons
mesh_terms: D002454:Cell Differentiation; D002986:Clinical Trials as Topic; D004789:Enzyme Activation; D031249:Erdheim-Chester Disease / Q000235:genetics* / Q000628:therapy*; D059472:Exome; D020558:GTP Phosphohydrolases / Q000235:genetics; D015894:Genome, Human; D005838:Genotype; D006646:Histiocytosis, Langerhans-Cell / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D017422:Sequence Analysis, DNA; D014972:Xanthogranuloma, Juvenile / Q000235:genetics* / Q000628:therapy*
chemical_list: D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human