Untranslated region rewiring defines a novel class of oncogene fusions.
TL;DR
This work defines a previously unrecognized class of oncogenic fusions that preserve protein structure but replace the 5' untranslated region (5' UTR), thereby rewiring translational regulation in cancer patients.
Abstract
Gene fusions in cancer are traditionally understood to generate hybrid proteins with altered functions that promote malignancy. Here, we define a previously unrecognized class of oncogenic fusions that preserve protein structure but replace the 5' untranslated region (5' UTR), thereby rewiring translational regulation. Using the MET oncogene as a paradigm, we show that 5' UTR-replacing fusions, identified across >200,000 cancer samples, increase MET protein abundance 5- to 10-fold without corresponding changes in mRNA levels. The resulting receptor remains correctly localized, ligand-responsive, and active, thereby promoting cell survival and motility. These fusion transcripts are detected following irradiation, documenting UTR rewiring in a post-treatment context. Beyond MET, similar 5' UTR-replacing fusions occur in FGFR1, JAK2, and NTRK2, where partner-derived 5 'UTRs are associated with reduced regulatory complexity and enhanced protein output. Together, our findings establish UTR rewiring as an overlooked mechanism of oncogene overexpression with implications for cancer genome annotation and precision oncology.
