Fusion transcripts: Unexploited vulnerabilities in cancer?

Gene fusions are an important class of mutations in several cancer types and include genomic rearrangements that fuse regulatory or coding elements from two different genes. Analysis of the genetics of cancers harboring fusion oncogenes and the proteins they encode have enhanced cancer diagnosis and in some cases patient treatment. However, the effect of the complex structure of fusion genes on the biogenesis of the resulting chimeric transcripts they express is not well studied. There are two potential RNA‐related vulnerabilities inherent to fusion‐driven cancers: (a) the processing of the fusion precursor messenger RNA (pre‐mRNA) to the mature mRNA and (b) the mature mRNA. In this study, we discuss the effects that the genetic organization of fusion oncogenes has on the generation of translatable mature RNAs and the diversity of fusion transcripts expressed in different cancer subtypes, which can fundamentally influence both tumorigenesis and treatment. We also discuss functional genomic approaches that can be utilized to identify proteins that mediate the processing of fusion pre‐mRNAs. Furthermore, we assert that an enhanced understanding of fusion transcript biogenesis and the diversity of the chimeric RNAs present in fusion‐driven cancers will increase the likelihood of successful application of RNA‐based therapies in this class of tumors. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease About one‐fifth of cancers harbor a fusion gene associated with disease pathology. The organization of fusion oncogenes can complicate the expression or structure of the mRNAs they express. The dependency of many cancer cells on the efficient biogenesis, and the continued presence of translatable fusion mRNAs offer potential RNA‐related therapeutic vulnerabilities.