title: High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis.
abstract: Langerhans cell histiocytosis (LCH) represents a clonal proliferation of Langerhans cells. BRAF V600E mutations have been identified in approximately 50% of cases. To discover other genetic mechanisms underlying LCH pathogenesis, we studied 8 cases of LCH using a targeted next-generation sequencing platform. An E102_I103del mutation in MAP2K1 was identified in one BRAF wild-type case and confirmed by Sanger sequencing. Analysis of 32 additional cases using BRAF V600E allele-specific polymerase chain reaction and Sanger sequencing of MAP2K1 exons 2 and 3 revealed somatic, mutually exclusive BRAF and MAP2K1 mutations in 18 of 40 (45.0%) and 11 of 40 (27.5%) cases, respectively. This is the first report of MAP2K1 mutations in LCH that occur in 50% of BRAF wild-type cases. The mutually exclusive nature of MAP2K1 and BRAF mutations implicates a critical role of oncogenic MAPK signaling in LCH. This finding may also have implications in the use of BRAF and MEK inhibitor therapy.
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI; and.
authors: Noah A
authors: NA
authors: Brown
authors: Department of Pathology, University of Chicago, Chicago, IL.
authors: Larissa V
authors: LV
authors: Furtado
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI; and.
authors: Bryan L
authors: BL
authors: Betz
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI; and.
authors: Mark J
authors: MJ
authors: Kiel
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI; and.
authors: Helmut C
authors: HC
authors: Weigelin
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI; and.
authors: Megan S
authors: MS
authors: Lim
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI; and.
authors: Kojo S J
authors: KS
authors: Elenitoba-Johnson
mesh_terms: D019943:Amino Acid Substitution; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000235:genetics; D006646:Histiocytosis, Langerhans-Cell / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D015995:Prevalence; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D014633:Valine / Q000235:genetics
chemical_list: D018698:Glutamic Acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D014633:Valine