Abstract
Gene fusions have long been considered hallmarks of cancer. Efforts into characterization of their prevalence, cause, and function have provided significant progress toward improvements in diagnosis, prognosis assessment, and treatment of numerous cancers. More recently, detection of intergenically spliced chimeric RNAs in cancer have spurred efforts to characterize these transcripts, anticipating similar successes in translation to the clinic. Discovery of chimeric RNAs in normal cells, especially those which precede canonical translocations such as PAX3-FOXO1 and JAZF1-JJAZ1, suggest that these physiologically-regulated transcripts may function as proto-oncogenic factors, in that their dysregulation can lead to cancer progression. These findings have given rise to conjecture regarding chimeric RNA-guided rearrangements giving rise to fusion genes, termed The Cart Before The Horse Hypothesis. Here, we provide context for the relationship between gene fusions, chimeric RNAs, and cancer, assemble evidence in support of the Cart Before The Horse Hypothesis, and discuss potential advantages of targeting chimeric RNAs in cancer treatment.