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Other RAS-MAPK pathway alterations
Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: April 30, 2025 · Captured 2026-09-09.
Selected source text with whitespace normalised. This Triangle page is not an NCI PDQ summary. Independent clinical review is pending.
Context: Langerhans Cell Histiocytosis / Genomics of LCH
Because RAS-MAPK pathway activation (elevated phosphor-ERK) can be detected in all LCH cases, including those without BRAF variants, the presence of genomic alterations in other components of the pathway was suspected. The following genomic alterations were identified:
MAP2K1 variants. Whole-exome sequencing on biopsy samples of BRAF-altered versus BRAF–wild-type LCH tissue revealed that 7 of 21 BRAF–wild-type specimens had MAP2K1 variants, while no BRAF-altered specimens had MAP2K1 variants.[13] The variants in MAP2K1 (which codes for MEK1) were activating, as indicated by their induction of ERK phosphorylation.[13]Another study showed MAP2K1 variants exclusively in 11 of 22 BRAF–wild-type cases.[18] One study showed that MAP2K1 and other variants associated with pediatric and adult LCH were mutually exclusive of BRAF variants.[19] The authors found a variety of variants in other pathways (e.g., JNK, RAS-ERK, and JAK-STAT) in pediatric and adult patients with BRAF V600E or MAP2K1 variants. Another study evaluated the kinase alterations and myeloid-associated variants in 73 adult patients with LCH.[20] They reported a median of two variants per adult patient, as opposed to children who usually have only one variant. BRAF V600E was found in 31%, BRAF indel in 29%, and MAP2K1 in 19% of patients with LCH. A variety of other protein kinase and related pathways were found in 89% of adult patients with LCH. MAP2K1 variants were exclusive of BRAF variants.
In-frame BRAF deletions and FAM73A::BRAF gene fusions. In-frame BRAF deletions and in-frame FAM73A::BRAF gene fusions have occurred in the group of BRAF V600E and MAP2K1 variant–negative cases.[12]
Source links and citations
In summary, studies support the universal activation of ERK in LCH. ERK activation in most cases of LCH is explained by BRAF and MAP2K1 alterations.[1,12,13] Altogether, these variants in the MAP kinase pathway account for nearly 80% of the causes of the universal activation of ERK in LCH.[1,12,13] The remaining cases have a range of variants that include small deletions in BRAF, BRAF gene fusions (discussed above), as well as variants in ARAF, MAP3K1, NRAS, ERBB3, PI3CA, CSF1R, and other rare targets.[19,17][Level of evidence C1]
Publication references
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Preserved source evidence · Independent clinical review pending · Not medical advice