Abstract
Alternative usage of transcript isoforms from the same gene has been hypothesized as an important feature in cancers. However, differential usage of gene transcripts between conditions (isoform switching) has not been comprehensively characterized in and across cancer types. To this end, we developed methods for identification and visualization of isoform switches with predicted functional consequences. Using these methods, we characterized isoform switching in RNA-seq data from >5,500 cancer patients covering 12 solid cancer types. Isoform switches with potential functional consequences were common, affecting approximately 19% of multiple transcript genes. Among these, isoform switches leading to loss of DNA sequence encoding protein domains were more frequent than expected, particularly in pancancer switches. We identified several isoform switches as powerful biomarkers: 31 switches were highly predictive of patient survival independent of cancer types. Our data constitute an important resource for cancer researchers, available through interactive web tools. Moreover, our methods, available as an R package, enable systematic analysis of isoform switches from other RNA-seq datasets.Implications: This study indicates that isoform switches with predicted functional consequences are common and important in dysfunctional cells, which in turn means that gene expression should be analyzed at the isoform level. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/9/1206/F1.large.jpg.Mol Cancer Res; 15(9); 1206-20. ©2017 AACR.
Highlights
The ability to produce different transcripts through alternative splicing (AS), alternative transcription start sites, and alternative transcription termination sites is a major determinant of the increased complexity of higher vertebrates [1]
Implications: This study indicates that isoform switches with predicted functional consequences are common and important in dysfunctional cells, which in turn means that gene expression should be analyzed at the isoform level
To exploit the advantages of both approaches, we tested each isoform for differential usage by comparing the isoform fractions (IF) values of tumor and healthy tissue samples using a paired Mann–Whitney U test for the paired samples and a standard Mann–Whitney U test for the unpaired analysis
Summary
The ability to produce different transcripts (gene isoforms) through alternative splicing (AS), alternative transcription start sites (aTSS), and alternative transcription termination sites (aTTS) is a major determinant of the increased complexity of higher vertebrates [1]. It is no surprise that gene isoform usage has an important role in many biological processes, including development, homeostasis, pluripotency, and apoptosis [5,6,7,8,9]. Isoforms are often tissue-specific and may alter the function, cellular localization, and stability of the corresponding RNA or protein [10, 11]. Differential usage of isoforms in different conditions, often referred to as isoform switching (Fig. 1A), can have substantial biological impact, caused by the difference in the functional potential of the two isoforms.
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