Background: The RAF1 gene encodes a kinase protein in the MAPK signaling pathway. Fusions involving RAF1 have been reported in solid tumors with a higher prevalence in melanoma, breast cancer, non-small cell lung cancer, and brain tumors. The fusions typically replace the N-terminal autoinhibitory domain with the 5’ partner genes leading to autonomous activation of RAF1 kinase. The efficacy of MEK inhibitors as a potential treatment for RAF1 fusion positive tumors is under investigation. Here we present a cohort of 8 RAF1 fusions involved in a spectrum of tumors in children and young adults. Methods: A retrospective search for tumors harboring RAF1 fusion was performed using our clinical database from 2016 to date. The RNA fusion analysis targets >700 exons of 117 genes for known and novel fusions. Additional genomic alterations, tumor type, and patient demographics were also collected. Results: A total of 8 cases positive for RAF1 fusion were identified from 2526 solid tumors including 6 brain tumors, 1 sarcoma, and 1 hepatoblastoma. Histologic diagnoses of the brain tumors were mostly low grade gliomas with no other driver mutations. Two pilocytic astrocytomas harbored RAF1 fusions without the pathognomonic KIAA1549:BRAF fusions. Although RAF1 fusions have been reported in rhabdomyosarcomas, it is the first time that a RAF1 fusion is associated with hepatoblastoma. 4 of the 8 RAF1 fusions identified are novel (noted with * in the table). The break points in RAF1 were at exon 7, 8, or 10, demonstrating the retention of the kinase domain. Conclusions: We report 8 RAF1 fusion positive solid tumors in children and young adults, mainly in low-grade gliomas. Although rare, the presence of a RAF1 fusion not only facilitates the tumor diagnosis but also provides genomic evidence for potential targeted therapies. References: 1. The AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discovery. 2017;7(8):818-831. 2. McEvoy CR et al. Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion. J Clin Invest. 2019; 129:1940-1945.

RAF1 (NM_002880.3); TMEM40 (NM_001284406); SOX6 (NM_033326.3); CAND2 (NM_012298.2); CRKL (NM_005207.3); QKI (NM_006775.2); DLG1 (NM_004087.2); ERC2 (NM_015576.2); TBL1XR1 (NM_024665.5).