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Fusion transcripts: Unexploited vulnerabilities in cancer?

Opinion

Natasha J. Caplen, Soumya Sundara Rajan, Carla Neckles

Published Online: Aug 13 2019

DOI: 10.1002/wrna.1562

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Abstract Gene fusions are an important class of mutations in several cancer types and include genomic rearrangements that fuse regulatory or coding elements from two different genes. Analysis of the genetics of cancers harboring fusion oncogenes and the proteins they encode have enhanced cancer diagnosis and in some cases patient treatment. However, the effect of the complex structure of fusion genes on the biogenesis of the resulting chimeric transcripts they express is not well studied. There are two potential RNA‐related vulnerabilities inherent to fusion‐driven cancers: (a) the processing of the fusion precursor messenger RNA (pre‐mRNA) to the mature mRNA and (b) the mature mRNA. In this study, we discuss the effects that the genetic organization of fusion oncogenes has on the generation of translatable mature RNAs and the diversity of fusion transcripts expressed in different cancer subtypes, which can fundamentally influence both tumorigenesis and treatment. We also discuss functional genomic approaches that can be utilized to identify proteins that mediate the processing of fusion pre‐mRNAs. Furthermore, we assert that an enhanced understanding of fusion transcript biogenesis and the diversity of the chimeric RNAs present in fusion‐driven cancers will increase the likelihood of successful application of RNA‐based therapies in this class of tumors. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease

Canonical and alternative splicing events for a representative fusion transcript. Boxes and solid lines indicate exons and introns, respectively. The dashed lines indicate possible splicing events in the context of exons adjacent to a fusion breakpoint

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Potential therapeutic approaches to target EWS‐FLI1 transcripts using nucleic acid analogues or small molecules. The representations of the mechanism of action of nucleic acid analogues are adapted with permission from Lieberman (). Copyright 2018 Springer Nature and encompass some of the major classes of RNA‐based drugs. (a) Antisense oligonucleotides that are typically single‐stranded with a central DNA gapmer region; (b) double‐stranded siRNAs; (c) miRNA mimics; and (d) aptamer‐based analogues such as aptamer‐siRNA conjugates. Representations of the mechanism of actions for (e) RNA‐binding small molecules that modulate the binding of an RNA binding protein (RBP) and (f) bifunctional small molecules that recruit a ribonuclease (RNase)

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(a) Schematic depictions of the EWSR1, FLI1, and EWS‐FLI1 genes. Indicated are the relative size of each exon (upper) and each intron (lower part of each panel). Genes and transcripts (not to scale) are shown 5 to 3′. (b) Schematic depiction of the putative splicing motifs in regions including and adjacent to EWSR1 exons 7 and 8 and FLI1 exon 6 that are involved in EWS‐FLI1 type 1 fusions. Representations are provided by Human Splicing Finder 3.1 (Desmet et al., ) for indicated regions within ENST00000406548 (EWSR1) or ENST00000527786 (FLI1)

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(a) Schematic depictions of representative transcripts expressed from fusion genes generated by chromosomal rearrangements (t11;22)(q24;q12) and t(21;22)(q21;q12) that disrupt the EWSR1 and FLI1 or ERG genes. (Adapted with permission from Sankar and Lessnick (). Copyright 2011 Elsevier) and COSMIC resources (COSMIC). (b) Candidate genes associated with canonical or alternative splicing identified by a RNAi screen of EWS‐FLI1 activity. The median seed corrected Z‐score obtained by the difference between Z_NROB1 and Z_CMV (three siRNAs per gene) for 35 genes that exhibited a selective decrease (Z‐score < −1) in the TC32‐NR0B1‐luc reporter when silenced. (See Pubchem BioAssay AID: 1159506 and Grohar et al., (2016))

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Schematic depictions of representative transcripts expressed from fusion genes generated by chromosomal rearrangements that disrupt (a) the EML4 and ALK genes (inv(2)(p21p23)). (Adapted from Sabir, Yeoh, Jackson, and Bayliss ()), (b) the BRD4 and NUTM1 genes (t(15;19)(q14;p13)) (Adapted with permission from Thompson‐Wicking et al. (). Copyright 2013 Springer Nature), and (c) the TMPRSS2 and ERG genes (del(21)(q22q22)). Genes and transcripts (not to scale) are shown 5 to 3′. (Adapted with permission from Clark et al. (). Copyright 2007 Springer Nature)

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Schematic depictions of representative transcripts expressed from fusion genes generated by chromosomal rearrangements that disrupt (a) the BCR and ABL genes (t(9;22)(q34;q11)). (Reprinted with permission from Deininger, Goldman, and Melo (). Copyright 2000 American Society of Hematology). (b) The RUNX1 and RUNX1T1 genes (ins(21;20)(q22;q11q11)). Genes and transcripts (not to scale) are shown 5 to 3′. (Adapted with permission from Lam and Zhang ())

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