MAPK/ERK signal pathway alterations in patients with Langerhans Cell Histiocytosis

Olga Novosad, Tanya Skrypets, Yan Pastushenko, Iryna Titorenko, Arina Martynchyk, Oksana Skachkova, Mariia Inomistova, Alex Gorbach, Nataliia Khranovska, Irina Kryachok



Background. Clinical outcomes of Langerhans Cell Histiocytosis (LCH) are highly variable forms.  It has been suggested that MAPK/ERK signaling pathway might be activated in LCH patients (pts).

Materials and Methods. We investigated KRAS, BRAF and NRAS mutations in patients with LCH by the qPCR analysis.

Results. 8 adult pts with LCH were treated at the National Cancer Institute, Kyiv, Ukraine. 5 and 3 patients received chemo plus radiation therapy and only chemotherapy, respectively (p<0.05). All patients received LCH–I study protocol, six cycles in average.

A BRAF c.1799T>A, p.V600E mutation was detected in 25% (2/8) cases: 1 patient had an early relapse in 6 months and 1 patient - stable disease. We didn’t find any of BRAF, KRAS or NRAS mutations in three pts with late relapses (in 15, 24 and 46 months). Notable, that KRAS mutations were not revealed in any LCH samples. The NRAS c.182A>G, p. Q61R mutation was found in two cases: one patient had LCH transformed to Hodgkin`s lymphoma; one patient had a refractory disease. Time-to-relapse (TTR) rate in patients with and without BRAF V600E gene mutation was 13 versus 28 months respectively, p<0.05. TTR was 31.3 versus 6.41 months in pts with absence and presence NRAS mutation, p<0.05. Multivariate analysis showed the presence of NRAS Q61R mutation was association with poor event-free survival in LCH pts with HR of 6.1 [95% (CI) 0.2-12.6, p=0.008]. 

Conclusion. BRAF and NRAS mutations in LCH suggest a possibility of disease being driven by the activation of the MAPK/ERK pathway. These oncogenic mutations provide new opportunities in understanding LCH pathogenesis and potential target therapy.

Klíčová slova

Langerhans Cell Histiocytosis, mutations, Prognostic Factors, relapse, survival.

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