Alternative transcription and alternative splicing in cancer

In recent years, the notion of “one gene makes one protein that functions in one signaling pathway” in mammalian cells has been shown to be overly simplistic. Recent genome-wide studies suggest that at least half of the human genes, including many therapeutic target genes, produce multiple protein isoforms through alternative splicing and alternative usage of transcription initiation and/or termination. For example, alternative splicing of the vascular endothelial growth factor gene (VEGFA) produces multiple protein isoforms, which display either pro-angiogenic or anti-angiogenic activities. Similarly, for the majority of human genes, the inclusion or exclusion of exonic sequences enhances the generation of transcript variants and/or protein isoforms that can vary in structure and functional properties. Many of the isoforms produced in this manner are tightly regulated during normal development but are misregulated in cancer cells. Altered expression of transcript variants and protein isoforms for numerous genes is linked with disease and its prognosis, and cancer cells manipulate regulatory mechanisms to express specific isoforms that confer drug resistance and survival advantages. Emerging insights indicate that modulating the expression of transcript and protein isoforms of a gene may hold the key to impeding tumor growth and act as a model for efficient targeting of disease-associated genes at the isoform level. This review highlights the role and regulation of alternative transcription and splicing mechanisms in generating the transcriptome, and the misuse and diagnostic/prognostic potential of alternative transcription and splicing in cancer.