Abstract
Gene fusions are appreciated as ideal cancer biomarkers and therapeutic targets. Chimeric RNAs are traditionally thought to be products of gene fusions, and thus, also cancer-specific. Recent research has demonstrated that chimeric RNAs can be generated by intergenic splicing in the absence of gene fusion, and such chimeric RNAs are also found in normal physiology. These new findings challenge the traditional theory of chimeric RNAs exclusivity to cancer, and complicates use of chimeric RNAs in cancer detection. Here, we provide an overview of gene fusions and chimeric RNAs, and emphasize their differences. We note that gene fusions are able to generate chimeric RNAs in accordance with the central dogma of biology, and that chimeric RNAs may also be able to influence the generation of the gene fusions per the "horse before the cart" hypothesis. We further expand upon the "horse before the cart" hypothesis, summarizing current evidence in support of the theory and exploring its potential impact on the field.