Abstract
Most mammalian genes are able to express several splice variants in a phenomenon known as alternative splicing. Serious alterations of alternative splicing occur in cancer tissues, leading to expression of multiple aberrant splice forms. Most studies of alternative splicing defects have focused on the identification of cancer-specific splice variants as potential therapeutic targets. Here, we examine instead the bulk of non-specific transcript isoforms and analyze their level of disorder using a measure of uncertainty called Shannon's entropy. We compare isoform expression entropy in normal and cancer tissues from the same anatomical site for different classes of transcript variations: alternative splicing, polyadenylation, and transcription initiation. Whereas alternative initiation and polyadenylation show no significant gain or loss of entropy between normal and cancer tissues, alternative splicing shows highly significant entropy gains for 13 of the 27 cancers studied. This entropy gain is characterized by a flattening in the expression profile of normal isoforms and is correlated to the level of estimated cellular proliferation in the cancer tissue. Interestingly, the genes that present the highest entropy gain are enriched in splicing factors. We provide here the first quantitative estimate of splicing disruption in cancer. The expression of normal splice variants is widely and significantly disrupted in at least half of the cancers studied. We postulate that such splicing disorders may develop in part from splicing alteration in key splice factors, which in turn significantly impact multiple target genes.
Highlights
The majority of mammalian genes produce alternative transcripts as part of their normal expression program [1,2,3,4]
RNA splicing is the process by which gene products are pieced together to form a mature messenger RNA
We show that overall splicing disorders are highly significant in many cancers, and that the extent of disorder may be correlated to the level of cell proliferation in each tumor
Summary
The majority of mammalian genes produce alternative transcripts as part of their normal expression program [1,2,3,4]. Mutations in cis-regulatory sequences lead to the abnormal expression of specific isoforms, as observed for example in the BRCA1 gene in breast and ovarian cancer [13]. Another class of event includes alterations of the mRNA processing machinery or its signalling pathway. These may affect the splicing of specific genes such as CD44 [14,15,16], but may cause wider perturbations of isoform expression as the processing of multiple genes can be simultaneously affected [17,18,19,20]. While most studies of splicing and cancer attempt to isolate ‘‘signature’’ splice variants with significant over-expression in disease cells, no published work to date has focused on the bulk of splicing disruption that potentially arises when the splicing machinery is impaired
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