Entropy Measures Quantify Global Splicing Disorders in Cancer

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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. RNA splicing is the process by which gene products are pieced together to form a mature messenger RNA (mRNA). In normal cells, RNA splicing is a tightly controlled process that leads to production of a well-defined set of mRNAs. Cancer cells, however, often produce aberrant, mis-spliced mRNAs. Such disorders have not been quantified to date. To this end, we use a well-known measure of disorder called Shannon's entropy. 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. Surprisingly, genes that control the splicing mechanism are unusually frequent among genes affected by splicing disorders. This suggests that cancer cells may withstand harmful chain reactions in which splicing defects in key regulatory genes would in turn cause extensive splicing damage. As mis-spliced mRNAs are widely studied for cancer diagnosis, awareness of these global disorders is important to distinguish reliable cancer markers from background noise.