Recurrent BRAF mutations in Langerhans cell histiocytosis.
Langerhans cell histiocytosis (LCH) has a broad spectrum of clinical behaviors; some cases are self-limited, whereas others involve multiple organs and cause significant mortality. Although Langerhans cells in LCH are clonal, their benign morphology and their lack (to date) of reported recurrent genomic abnormalities have suggested that LCH may not be a neoplasm. Here, using 2 orthogonal technologies for detecting cancer-associated mutations in formalin-fixed, paraffin-embedded material, we identified the oncogenic BRAF V600E mutation in 35 of 61 archived specimens (57%). TP53 and MET mutations were also observed in one sample each. BRAF V600E tended to appear in younger patients but was not associated with disease site or stage. Langerhans cells stained for phospho-mitogen-activated protein kinase kinase (phospho-MEK) and phospho-extracellular signal-regulated kinase (phospho-ERK) regardless of mutation status. High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors.
Badalian-Very
Gayane
G
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA.
Vergilio
Jo-Anne
JA
Degar
Barbara A
BA
MacConaill
Laura E
LE
Brandner
Barbara
B
Calicchio
Monica L
ML
Kuo
Frank C
FC
Ligon
Azra H
AH
Stevenson
Kristen E
KE
Kehoe
Sarah M
SM
Garraway
Levi A
LA
Hahn
William C
WC
Meyerson
Matthew
M
Fleming
Mark D
MD
Rollins
Barrett J
BJ
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D018949:Antigens, CD1 / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006646:Histiocytosis, Langerhans-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D055815:Young Adult
D018949:Antigens, CD1; C419393:CD1a antigen; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases