Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data

Lynnette Fernandez-Cuesta, Ruping Sun, Roopika Menon, Julie George, Susanne Lorenz, Leonardo A Meza-Zepeda, Martin Peifer, Dennis Plenker, Johannes M Heuckmann, Frauke Leenders, Thomas Zander, Ilona Dahmen, Mirjam Koker, Jakob Schöttle, Roland T Ullrich, Janine Altmüller, Christian Becker, Peter Nürnberg, Henrik Seidel, Diana Böhm, Friederike Göke, Sascha Ansén, Prudence A Russell, Gavin M Wright, Zoe Wainer, Benjamin Solomon, Iver Petersen, Joachim H Clement, Jörg Sänger, Odd-Terje Brustugun, Åslaug Helland, Steinar Solberg, Marius Lund-Iversen, Reinhard Buettner, Jürgen Wolf, Elisabeth Brambilla, Martin Vingron, Sven Perner, Stefan A Haas, Roman K Thomas

Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline) (https://github.com/ruping/TRUP), a computational approach that combines split-read and read-pair analysis with de novo assembly for the identification of chimeric transcripts in cancer specimens. We apply TRUP to RNA-seq data of different tumor types, and find it to be more sensitive than alternative tools in detecting chimeric transcripts, such as secondary rearrangements in EML4-ALK-positive lung tumors, or recurrent inactivating rearrangements affecting RASSF8.