Oncogenic properties via MAPK signaling of the SOX5‐RAF1 fusion gene identified in a wild‐typeNRAS/BRAF giant congenital nevus

We recently reported an RAF rearrangement without NRAS or BRAF mutations in lesions from Giant Congenital Melanocytic Nevi (CMN). The new gene fusion involves the 5'-end of the promoter-containing N terminus of the SOX5 gene fused to exons 7-16 of the 3'-end of RAF1 gene leading to a SOX5-RAF1 fusion transcript which loses the auto-inhibitory CR1 domain but retains the complete in-frame coding sequence for the C-Terminal kinase domain of the RAF1. Stable expression of SOX5-RAF1 fusion induced growth factor-independent cell growth in murine hematopoietic Ba/F3 cells and melan-a immortalized melanocytes. Besides, it led to the transformation of both Ba/F3 and NIH 3T3 cells as revealed by colony formation assays. Furthermore, its expression results in MAPK activation assessed by increased levels of p-ERK protein in the cytosol of transduced cells. Treatment with Sorafenib and UO126 inhibited proliferation of Ba/F3-SOX5-RAF1 cells in the absence of IL3 but not the PLX 4720, a specific inhibitor of BRAF. Moreover, the tumorigenic and metastatic capacities of SOX5-RAF1 were assessed in vivo. These results indicate that SOX5-RAF1, a driver event for CMN development, has oncogenic capacity. Thus, sequencing of CMN transcriptomes may lead to the identification of this druggable fusion and interfere with the progression toward melanoma.