Chimeric RNAs and their implications in cancer

Abstract

Chimeric RNAs have been believed to be solely produced by gene fusions resulting from chromosomal rearrangement, thus unique features of cancer. Detected chimeric RNAs have also been viewed as surrogates for the presence of gene fusions. However, more and more research has demonstrated that chimeric RNAs in general are not a hallmark of cancer, but rather widely present in non-cancerous cells and tissues. At the same time, they may be produced by other mechanisms other than chromosomal rearrangement. The field of non-canonical chimeric RNAs is still in its infancy, with many challenges ahead, including the lack of a unified terminology. However, we believe that these non-canonical chimeric RNAs will have significant impacts in cancer detection and treatment.

Figure 1. Chimeric RNA centric view

Chimeric RNAs can be generated by gene fusion, trans-splicing, and cis-splicing between adjacent genes (cis-SAGe). They can function as chimeric proteins, long non-coding chimeric RNAs (lnccRNA), or affect parental gene expression. Traditionally, they have been thought to be specific to cancer. However, increasing numbers are being found in normal physiology.

Figure 2. Three known generating mechanisms for chimeric RNAs

Exons are depicted as blocks, and introns are indicated by lines. (A) Chromosomal rearrangement including translocation, deletion, and inversion. Shown here is a case of translocation. Gene fragments from different genomic loci are juxtaposed together. (B) RNA trans-splicing. Two separate pre-mRNA transcripts are spliced together. (C) cis-splicing between adjacent genes. The transcription machinery reads through two neighboring genes, and the exons from the two genes are spliced together.

Figure 3. Example of the landscape of chimeric RNAs

The data is from our analysis of over 7000 RNA-Seq samples covering 53 different tissues. (A) Chimeric RNAs can be grouped by different criteria. They can be grouped according to the location of parental genes, the fusion junction site relative to exons, and protein coding reading frames. (B) Chimeric RNAs may have different tissue distributions.