New somatic BRAF splicing mutation in Langerhans cell histiocytosis

作者：Heritier Sebastien^*; Helias Rodzewicz Zofia; Chakraborty Rikhia; Sengal Amel G; Bellanne Chantelot Christine; Thomas Caroline; Moreau Anne; Fraitag Sylvie; Allen Carl E; Donadieu Jean; Emile Jean Francois

来源：Molecular Cancer, 2017, 16(1): 115.

DOI：10.1186/s12943-017-0690-z

• Langerhans cell histiocytosis
• BRAF
• Splicing mutation
• Targeted therapy

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with constitutive activation of the MAPKinase RAS-RAF-MEK-ERK cell signaling pathway. We analyzed 9 LCH cases without BRAF(V600) and MAP2K1 mutations by whole exome sequencing. We identified a new somatic BRAF splicing mutation in 2 cases. Both cases were childhood single system (SS) LCH cases, with self-healing outcome of the bone lesions. This mutant consisted in a 9 base pair duplication (c. 1511_1517 + 2 duplication), encoding for a predicted mutant protein with insertion of 3 amino acids (p. Arg506_Lys507insLeuLeuArg) in the N-terminal lobe of the kinase domain of BRAF. Transient expression of the c. 1511_1517 + 2dup BRAF mutant in HEK293 cells enhanced MAPKinase pathway activation, and was not inhibited by vemurafenib but was inhibited by PLX8394, a second-generation BRAF inhibitor able to inhibit signaling of BRAF monomers and dimers. Future LCH molecular screening panel should include this new mutation to better define its prevalence in LCH and its restriction to autoregressive bone SS LCH.

• 出版日期2017-7-6