Abstract
Recurrent fusion transcripts, which are one of the characteristic hallmarks of cancer, arise either from chromosomal rearrangements or from transcriptional errors in splicing. DNA rearrangements include intrachromosomal or interchromosomal translocation, tandem duplication, deletion, inversion, or result from chromothripsis, which causes complex rearrangements. In addition, fusion proteins can be created through transcriptional read-through. Fusion genes can be transcribed to fusion transcripts and translated to chimeric proteins, with many having demonstrated transforming activities through multiple mechanisms in cells. Fusion proteins represent novel therapeutic targets and diagnostic biomarkers of diagnosis, disease status, or progression. This review focuses on the mechanisms underlying the formation of oncogenic fusion genes and transcripts and their impact on the pathobiology of epithelial tumors.
Highlights
Three decades’ worth of accumulating data have shown that chromosomal rearrangements, including fusion genes, are frequent events and can act as genetic drivers of hematologic malignancies and mesenchymal tumors [1,2,3]
Fusion genes that disrupt transcription factor genes can result in chimeric proteins that have enhanced, repressed, or aberrant transcriptional activity
Fusion genes that disrupt tyrosine kinase can result in chimeric proteins with aberrant tyrosine kinase activity promoting downstream signaling pathways
Summary
Three decades’ worth of accumulating data have shown that chromosomal rearrangements, including fusion genes, are frequent events and can act as genetic drivers of hematologic malignancies and mesenchymal tumors [1,2,3]. As seen in prostate cancer, the forced expression of normal proteins (i.e. 3′ gene, ETS family of transcription factors) through an androgen-responsive promoter (TMPRSS2, a transmembrane serine protease) or by fusion to ubiquitous promoters results in overexpression of a wild-type protein [17, 25,26,27].
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