title: MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis.
abstract: Langerhans cell histiocytosis (LCH) is now understood to be a neoplastic disease in which over 50% of cases have somatic activating mutations of BRAF. However, the extracellular signal-related (ERK) pathway is activated in all cases including those with wild type BRAF alleles. Here, we applied a targeted massively parallel sequencing panel to 30 LCH samples to test for the presence of additional genetic alterations that might cause ERK pathway activation. In 20 BRAF wild type samples, we found 3 somatic mutations in MAP2K1 (MEK1) including C121S and C121S/G128D in the kinase domain, and 56_61QKQKVG>R, an in-frame deletion in the N-terminal regulatory domain. All three variant proteins constitutively phosphorylated ERK in in vitro kinase assays. The C121S/G128D and 56_61QKQKVG>R variants were resistant to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib in vitro. Within the entire sample set, we found 3 specimens with mutations in MAP3K1 (MEKK1), including two truncation mutants, T779fs and T1481fs; T1481fs encoded an unstable and nonfunctional protein when expressed in vitro. T779fs was present in a specimen carrying BRAF V600E. The third variant was a single nucleotide substitution, E1286V, which was fully functional and is likely a germline polymorphism. These results indicate that LCH cells can harbor additional genetic alterations in the RAS-RAF-MEK pathway which, in the case of MAP2K1, may be responsible for ERK activation in a wild type BRAF setting. The resistance of some of these variants to trametinib may also have clinical implications for the combined use of RAF and MEK inhibitors in LCH.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: David S
authors.initials: DS
authors.lastname: Nelson
authors.forename: Astrid
authors.initials: A
authors.lastname: van Halteren
authors.forename: Willemijn T
authors.initials: WT
authors.lastname: Quispel
authors.forename: Cor
authors.initials: C
authors.lastname: van den Bos
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
authors.forename: Bhumi
authors.initials: B
authors.lastname: Patel
authors.forename: Gayane
authors.initials: G
authors.lastname: Badalian-Very
authors.forename: Paul
authors.initials: P
authors.lastname: van Hummelen
authors.forename: Matthew
authors.initials: M
authors.lastname: Ducar
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Laura E
authors.initials: LE
authors.lastname: MacConaill
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
authors.forename: Barrett J
authors.initials: BJ
authors.lastname: Rollins
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D006646:Histiocytosis, Langerhans-Cell / Q000235:genetics*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human