Abstract 954: The landscape of kinase fusions in cancer

Abstract

Abstract Human cancer genomes harbor a variety of alterations leading to the deregulation of key pathways in tumor cells. The genomic characterization of tumors has uncovered numerous genes recurrently mutated, deleted or amplified, but gene fusions have not been studied as extensively. Kinase fusions represent ideal targets for the development of cancer drugs because they often confer oncogenic dependency in hematopoietic and solid malignancies as demonstrated by the success of several kinase inhibitors. For example, imatinib induces remission in leukemia patients who are positive for BCR-ABL1 fusions, and crizotinib and ceritinib have produced significant clinical benefit in patients with lung adenocarcinomas and mesenchymal tumors harboring ALK fusions. We have developed heuristics for reliably detecting gene fusion events in RNA-seq data sets and apply them to nearly 9,000 samples from The Cancer Genome Atlas. Fusions between any two genes were identified based on the number of chimeric reads and split reads. Then a number of filtering criteria were applied to flag false positive and non-functional fusions, including the removal of kinase fusions observed in a panel of more than 3,500 normal samples from diverse origins. Finally, we reviewed all recurrent kinase fusions manually to identify putative oncogenic drivers with distinctive characteristics of functional kinase fusions. We thereby were able to recapitulate most known translocation events in solid tumors (i.e., ALK, BRAF, EGFR, FGFR1, 2 and 3, NTRK1, 2 and 3, PDGFRA, PRKCA, RAF1, RET, ROS1). Interestingly, we identified new tumor types harboring such fusions and discovered several novel fusion partners for these kinases. We also detected several low-frequency, pan-cancer kinase fusion events, for example in the neurotrophic tyrosine receptor kinases NTRK1, NTRK2 and NTRK3, that drive tumorigenesis in a small fraction of multiple cancers, regardless of tissue type. Using our computational pipeline, we identified several novel and recurrent kinase fusions involving the MET proto-oncogene and PIK3CA. These bona fide oncogenes have not been shown previously to be activated by fusion events. Our analysis also uncovered novel, recurrent fusions in kinases with no known tumorigenic genomic alterations (e.g., FGR and PKN1), potentially resulting in active and oncogenic fusion proteins that represent putative targets for drug discovery. These findings have immediate diagnostic and clinical implications and expand the therapeutic options for cancer patients, as approved or exploratory drugs exist for many of these kinases. Citation Format: Nicolas Stransky, Ethan Cerami, Stefanie Schalm, Joseph L. Kim, Klaus Hoeflich, Christoph Lengauer. The landscape of kinase fusions in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 954. doi:10.1158/1538-7445.AM2015-954