High prevalence of somatic MAP2K1 mutations in BRAF V600E–negative Langerhans cell histiocytosis

NA Brown, LV Furtado, BL Betz, MJ Kiel… - Blood, The Journal …, 2014 - ashpublications.org
NA Brown, LV Furtado, BL Betz, MJ Kiel, HC Weigelin, MS Lim, KSJ Elenitoba-Johnson
Blood, The Journal of the American Society of Hematology, 2014ashpublications.org
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 …
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.
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