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

Clinical outcomes of Langerhans cell histiocytosis (LCH) are highly variable. It has been suggested that mitogen-activated protein kinase (MAPK) /extracellular signal-regulated kinases (ERK) signaling pathway might be activated in LCH patients. We investigated KRAS, BRAF and NRAS mutations in patients with LCH by qPCR. Eight adult patients with LCH were treated at the National Cancer Institute, Kiev, Ukraine. Five patients received chemo plus radiation therapy and three patients received only chemotherapy, resp. (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) of cases - 1 patient had an early relapse in 6 months, and 1 patient - stable disease. We did not find any BRAF, KRAS or NRAS mutations in three patients with late relapses (in 15, 24 and 46 months). Notably, 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 Hodgkins lymphoma, one patient had a refractory disease. Time to relapse rate (TTR) in patients with and without BRAF V600E gene mutation was 13 vs. 28 months, resp. (p < 0.05). TTR was 31.3 vs. 6.41 months in patients with absence and presence of NRAS mutation, p < 0.05. Multivariate analysis showed the presence of NRAS Q61R mutation was associated with poor event-free survival in LCH patients with HR of 6.1 (95% CI 0.2-12.6; p = 0.008). BRAF and NRAS mutations in LCH suggest a possibility of the disease being driven by the activation of the MAPK/ERK pathway. These oncogenic mutations provide new opportunities in understanding LCH pathogenesis and may be a potential target of therapy.Key words: Langerhans cell histiocytosis - mutations - prognostic factors - relapse - survival.