Cancer fusion transcripts with human non-coding RNAs

Abstract

Cancer chimeric, or fusion, transcripts are thought to most frequently appear due to chromosomal aberrations that combine moieties of unrelated normal genes. When being expressed, this results in chimeric RNAs having upstream and downstream parts relatively to the breakpoint position for the 5'- and 3'-fusion components, respectively. As many other types of cancer mutations, fusion genes can be of either driver or passenger type. The driver fusions may have pivotal roles in malignisation by regulating survival, growth, and proliferation of tumor cells, whereas the passenger fusions most likely have no specific function in cancer. The majority of research on fusion gene formation events is concentrated on identifying fusion proteins through chimeric transcripts. However, contemporary studies evidence that fusion events involving non-coding RNA (ncRNA) genes may also have strong oncogenic potential. In this review we highlight most frequent classes of ncRNAs fusions and summarize current understanding of their functional roles. In many cases, cancer ncRNA fusion can result in altered concentration of the non-coding RNA itself, or it can promote protein expression from the protein-coding fusion moiety. Differential splicing, in turn, can enrich the repertoire of cancer chimeric transcripts, e.g. as observed for the fusions of circular RNAs and long non-coding RNAs. These and other ncRNA fusions are being increasingly recognized as cancer biomarkers and even potential therapeutic targets. Finally, we discuss the use of ncRNA fusion genes in the context of cancer detection and therapy.

Keywords: cancer; carcinogenesis; chimeric RNAs; chromosomal rearrangements; fusion oncogenes; lncRNA; long non-coding RNA.

Figure 1

Major fusion genes and chimeric RNA formation mechanisms. Exons and introns are shown as blocks and lines, accordingly. (A) Structural rearrangements of chromosomes resulting in the formation of fusion genes include balanced rearrangements that comprise translocations, inversions, and insertions with no loss or gain of genetic material. Unbalanced rearrangements comprise alterations causing extra or missing genetic fragments, including deletions, duplications, and chromothripsis. (B) Non-structural rearrangements form non-canonical chimeric RNAs through alternative splicing, without structural rearrangements on the DNA level, including cis-splicing of adjacent genes (cis-SAGe) and trans-splicing, which can potentially involve two different pre-mRNA molecules and can be either intergenic or intragenic.

Figure 2

Schematic representation of major types of regulatory ncRNAs and their functions. Aside from housekeeping ncRNA such as transfer RNAs and ribosomal RNAs, other regulatory ncRNAs can be classified by their size. long ncRNAs are larger than 200 nucleotides and can reach up to thousands of nucleotides of length. Small ncRNAs usually are under 200 nucleotides in length, these include small nucleolar RNAs, small nuclear RNAs, PIWI-interacting RNAs, micro RNAs and short interfering RNAs (siRNA).

Figure 3

Illustrates possible scenarios by which chromosomal rearrangements involve ncRNAs or directly alter ncRNA expression, (A) The regulatory domains of the protein-coding gene may get substituted with the regulatory elements of the ncRNA host gene, thereby leading to dysregulated protein expression. Alternatively, (B) The protein-coding gene regulatory regions could either enhance the activation or trigger the silencing of the ncRNA upon exchange with the host gene regulatory elements. ncRNA-convergent fusions may arise when a single ncRNA host gene fuses with diverse genes, establishing a fusion cluster with the purpose of modulating ncRNA expression. (C) A fusion event between two protein-coding genes can generate novel chimeric ncRNAs, such as fusion circRNAs and lnccRNAs, that can serve as competitive endogenous RNAs possessing regulatory miRNA binding sites, thereby competing with native transcripts for miRNA binding. (D) Ultimately, an alteration in the regulatory domains consequent to a fusion event can lead to downstream dysregulation of ncRNA expression. NCG, Non-coding gene; PCG, Protein coding gene; lnccRNAs, long non-coding chimeric RNAs.