Abstract
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.
Highlights
Over the past decade, there has been tremendous development in the field of chimeric RNA discovery, pursuing identification of novel biomarkers and therapeutic targets in cancer [1,2,3,4]
Chimeric RNAs produced by chromosomal rearrangement are common features of neoplasia
Chimeric RNAs detected in normal tissues and cells such as the ones we detected in Genotype-Tissue Expression (GTEx) are presumably produced in the absence of chromosomal rearrangement
Summary
There has been tremendous development in the field of chimeric RNA discovery, pursuing identification of novel biomarkers and therapeutic targets in cancer [1,2,3,4]. RNA-seq data availability from large projects such as TCGA [5] allows for high throughput discovery of chimeric RNAs in cancer [6,7,8,9,10]. Recent research has validated the existence of chimeric RNAs in non-cancerous cells and tissues [14,15,16,17,18,19,20]. These findings highlight the need to establish a true baseline of chimeric RNAs in normal physiology before cancer-specific fusion events can be identified. There are limitations of that study, including: sample selection and curation to ensure proper histology of tissues; sample size; and the stringency of filters for recurrent events
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