title: Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis.
abstract: Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder characterized by lesions composed of pathological CD207(+) dendritic cells with an inflammatory infiltrate. BRAFV600E remains the only recurrent mutation reported in LCH. In order to evaluate the spectrum of somatic mutations in LCH, whole exome sequencing was performed on matched LCH and normal tissue samples obtained from 41 patients. Lesions from other histiocytic disorders, juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease were also evaluated. All of the lesions from histiocytic disorders were characterized by an extremely low overall rate of somatic mutations. Notably, 33% (7/21) of LCH cases with wild-type BRAF and none (0/20) with BRAFV600E harbored somatic mutations in MAP2K1 (6 in-frame deletions and 1 missense mutation) that induced extracellular signal-regulated kinase (ERK) phosphorylation in vitro. Single cases of somatic mutations of the mitogen-activated protein kinase (MAPK) pathway genes ARAF and ERBB3 were also detected. The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in cell culture and primary tumor models was dependent on the specific LCH mutation. The findings of this study support a model in which ERK activation is a universal end point in LCH arising from pathological activation of upstream signaling proteins.
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX;
authors.forename: Rikhia
authors.initials: R
authors.lastname: Chakraborty
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Hampton
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX;
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Shen
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Division of Pediatric Hematology-Oncology, Department of Pediatrics.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Simko
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX;
authors.forename: Albert
authors.initials: A
authors.lastname: Shih
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX;
authors.forename: Harshal
authors.initials: H
authors.lastname: Abhyankar
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Program in Translational Biology and Molecular Medicine, and.
authors.forename: Karen Phaik Har
authors.initials: KP
authors.lastname: Lim
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Lisa
authors.initials: L
authors.lastname: Trevino
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Ninad
authors.initials: N
authors.lastname: Dewal
authors.affiliation: Human Genome Sequencing Center.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center.
authors.forename: Harshavardhan
authors.initials: H
authors.lastname: Doddapaneni
authors.affiliation: Human Genome Sequencing Center.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: Linghua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Division of Pediatric Hematology-Oncology, Department of Pediatrics.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lupo
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Division of Pediatric Hematology-Oncology, Department of Pediatrics, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX;
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.affiliation: Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Bonilla
authors.affiliation: Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Dwyer
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Immunology Institute, and.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Berres
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine, New York, NY.
authors.forename: Poulikos I
authors.initials: PI
authors.lastname: Poulikakos
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Immunology Institute, and.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Division of Pediatric Hematology-Oncology, Department of Pediatrics.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: McClain
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Division of Pediatric Hematology-Oncology, Department of Pediatrics, Program in Translational Biology and Molecular Medicine, and.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Allen
authors.affiliation: Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Department of Molecular and Human Genetics, Human Genome Sequencing Center, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Program in Translational Biology and Molecular Medicine, and.
authors.forename: D Williams
authors.initials: DW
authors.lastname: Parsons
mesh_terms: D003713:Dendritic Cells / Q000378:metabolism; D018450:Disease Progression; D031249:Erdheim-Chester Disease / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006646:Histiocytosis, Langerhans-Cell / Q000235:genetics* / Q000378:metabolism*; D015618:Histiocytosis, Sinus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism*; D014972:Xanthogranuloma, Juvenile / Q000235:genetics / Q000378:metabolism
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human