The spectrum of RAF1 fusion positive solid tumors in children and young adults.

Abstract

e22013 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.