Abstract
Dysregulation of alternative splicing (AS) is one of the molecular hallmarks of cancer, with splicing alteration of numerous genes in cancer patients. However, studying splicing mis-regulation in cancer is complicated by the large noise generated from tissue-specific splicing. To obtain a global picture of cancer-specific splicing, we analyzed transcriptome sequencing data from 1149 patients in The Cancer Genome Atlas project, producing a core set of AS events significantly altered across multiple cancer types. These cancer-specific AS events are highly conserved, are more likely to maintain protein reading frame, and mainly function in cell cycle, cell adhesion/migration, and insulin signaling pathways. Furthermore, these events can serve as new molecular biomarkers to distinguish cancer from normal tissues, to separate cancer subtypes, and to predict patient survival. We also found that most genes whose expression is closely associated with cancer-specific splicing are key regulators of the cell cycle. This study uncovers a common set of cancer-specific AS events altered across multiple cancers, providing mechanistic insight into how splicing is mis-regulated in cancers.
Highlights
Most human genes undergo alternative splicing (AS) to produce multiple isoforms with different biological properties
To increase the statistical power of our analyses, we selected three types of cancers that have a relatively large number of paired normal controls. These tissue types are sufficiently different to enable us to filter out tissue-specific splicing, as most identified AS events are altered in only a single type of cancer (Figure 1B)
The AS events significantly altered in all three cancer types include many genes whose splicing was known to play critical roles in cancer development, such as the CD44 [8], NUMB [40, 41], and FN1 [42]
Summary
Most human genes undergo alternative splicing (AS) to produce multiple isoforms with different biological properties. This process is tightly controlled across different tissues and developmental stages, and dysregulation of AS is closely associated with various human diseases including cancer [1, 2]. CD44 is a key mediator of cell-cell and cell-matrix interactions, migration and invasion [5], and different splicing isoforms of CD44 have been linked with tumor evasion and metastasis in many cancers [6,7,8]. Other well-documented cases include the apoptosis regulator Bcl-x, which can shift its splicing from pro-apoptotic into anti-apoptotic isoforms in cancers [9]
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