Chimeric RNAs and their encoded proteins have been traditionally viewed as unique features of neoplasia, and have been used as biomarkers and therapeutic targets for multiple cancers. Recent studies have demonstrated that chimeric RNAs also exist in non-cancerous cells and tissues, although large-scale, genome-wide studies of chimeric RNAs in non-diseased tissues have been scarce. Here, we explored the landscape of chimeric RNAs in 9495 non-diseased human tissue samples of 53 different tissues from the GTEx project. Further, we established means for classifying chimeric RNAs, and observed enrichment for particular classifications as more stringent filters are applied. We experimentally validated a subset of chimeric RNAs from each classification and demonstrated functional relevance of two chimeric RNAs in non-cancerous cells. Importantly, our list of chimeric RNAs in non-diseased tissues overlaps with some entries in several cancer fusion databases, raising concerns for some annotations. The data from this study provides a large repository of chimeric RNAs present in non-diseased tissues, which can be used as a control dataset to facilitate the identification of true cancer-specific chimeras.
Gene fusions are considered hallmarks of cancer which can be produced by chromosomal rearrangements. These DNA-level fusion events may result in the expression of chimeric RNAs; however, chimeric RNAs can be also produced by intergenic splicing events. Chimeric transcripts created by the latter mechanism are regulated at the transcriptional level and thus present additional modes of action and regulation. They have demonstrated importance in normal cell physiology, and their dysregulation can induce oncogenesis and impact cell differentiation. In this review, we outline proven mechanisms through which intergenically spliced chimeric RNAs are involved in carcinogenesis. We highlight their similarity to canonical chimeric RNAs resulting from gene fusions as well as their unique qualities. Additionally, we review known roles of chimeric RNA in cell differentiation and propose means through which chimeric RNAs may be valuable as stage-specific markers or as targets for expression profiling.
Gene fusions and their chimeric products are typically considered hallmarks of cancer. However, recent studies have found chimeric transcripts in non-cancer tissues and cell lines. In addition, efforts to annotate structural variation at large scale have found examples of gene fusions with potential to produce chimeric transcripts in normal tissues. In this report, we provide a means for targeting population-specific chimeric RNAs to enrich for those generated by gene fusion events. We identify 57 such chimeric RNAs from the GTEx cohort, including SUZ12P1-CRLF3 and TFG-ADGRG7, whose distribution we assessed across the populations of the 1000 Genomes Project. We reveal that SUZ12P1-CRLF3 results from a common complex structural variant in populations with African heritage, and identify its likely mechanism for formation. Additionally, we utilize a large cohort of clinical samples to characterize the SUZ12P1-CRLF3 chimeric RNA, and find an association between the variant and indications of Neurofibramatosis Type I. We present this gene fusion as a case study for identifying hard-to-find and potentially functional structural variants by selecting for those which produce population-specific fusion transcripts.
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