Khuong-Quang, D.-A.Brown, L.M.Wong, M.Mayoh, C.Sexton-Oates, A.Kumar, A.Pinese, M.Nagabushan, S.Lau, L.Ludlow, L.E.Gifford, A.J.Rodriguez, M.Desai, J.Fox, S.B.Haber, M.Ziegler, D.S.Hansford, J.R.Marshall, G.M.Cowley, M.J.Ekert, P.G.2024-01-092024-01-092020Cold Spring Harbor Molecular Case Studies, 2020; 6(6):a005710-1-a005710-172373-28732373-2873https://hdl.handle.net/2440/140338The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase (NTRK) family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L–NTRK fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the SPECC1L–NTRK2 fusion directly from a patient sample and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by SPECC1L–NTRK2 expression are sensitive to a TRK inhibitor drug. We report here that SPECC1L–NTRK fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect NTRK fusions, these techniques may be of benefit when NTRK fusions are not suspected on clinical grounds or not identified by other methods.en© 2020 Khuong-Quang et al. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.Biomarkers, TumorBrain NeoplasmsCentral Nervous System NeoplasmsChildGene Expression Regulation, NeoplasticHumansInfantMembrane GlycoproteinsOncogene Proteins, FusionPhosphoproteinsProtein Kinase InhibitorsReceptor, trkAReceptor, trkBSarcomaWhole Genome SequencingHumansSarcomaCentral Nervous System NeoplasmsBrain NeoplasmsReceptor, trkAReceptor, trkBMembrane GlycoproteinsOncogene Proteins, FusionPhosphoproteinsProtein Kinase InhibitorsGene Expression Regulation, NeoplasticChildInfantFemaleMaleBiomarkers, TumorWhole Genome SequencingJournal article10.1101/mcs.a0057102024-01-09601948Hansford, J.R. [0000-0001-7733-383X]