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LCH : Molecular Genetics

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Molecular Alterations in Langerhans Cell Histiocytosis (LCH): Langerhans cells (LCs) that accumulate in various tissues and organs in LCH share genetic similarities to the bone marrow-derived dendritic cell precursors and are not derived from skin LCs. Mutations in various genes of mitogen-activated protein kinase (MAPK) pathway in hematopoietic progenitor cells appear to underline the pathogenesis of LCH. Almost 80% of LCH patients have one or more of these mutations.

BRAF V600E: Activating BRAF V600E mutations are found in 55% to 60% of cases of LCH. They are more common in multisystem LCH than in patients with unifocal disease and associated with a higher risk of relapse. BRAF protein is a key component of MAPK (RAS-RAF-MEK-ERK) signaling pathway that activates transcription factors required for cell growth and proliferation. BRAF V600E mutations lead to constitutive activation of MEK and ERK causing uncontrolled growth. Besides tissue specimens, BRAF V600E mutations can be detected using allele-specific real-time PCR or digital droplet PCR in circulating cell-free DNA obtained from peripheral blood (so-called liquid biopsy) of LCH patients. In addition to V600E, several other BRAF mutations have been identified with whole exome/genome analysis using next-generation sequencing.

MAP2K1:The 2nd most common mutation in LCH is found in MAP2K1 gene, also a component of the MAPK pathway and located downstream of BRAF. About 25% of LCH cases show somatic MAP2K1 mutations, usually in BRAF germline (wild type) cases. These mutations activate ERK1 and ERK2 and lead to constitutive activation of MAPK signaling pathway. Other MAPK pathway genes such as ARAF and MAP3K1 are less commonly mutated.

PI3K-AKT-mTOR PATHWAY: This intracellular signaling pathway may also play a role in the pathogenesis of LCH. PIK3CA is an activating somatic mutation that leads to constitutive activation of the PI3K pathway. Other mutations include PICK1 and PIK3R2.

RARE MUTATIONS: Less common mutations occur in TP53, KRAS, and tyrosine kinase receptor ERBB3.

This diagram of MAPK and PI3K pathways shows mutations (in red) found in LCH. Image source: Masayuki Kobayashi & Arinobu Tojo. Langerhans Cell Histiocytosis in Adults : Advances in Pathophysiology and Treatment. Cancer Science, Dec. 2018, Vol. 109, Issue 12, p. 3707-3713; used under Creative Commons Attribution-NonCommercial 4.0 International License

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