Abstract
Alternative splicing changes are frequently observed in cancer and are starting to be recognized as important signatures for tumor progression and therapy. However, their functional impact and relevance to tumorigenesis remain mostly unknown. We carried out a systematic analysis to characterize the potential functional consequences of alternative splicing changes in thousands of tumor samples. This analysis revealed that a subset of alternative splicing changes affect protein domain families that are frequently mutated in tumors and potentiallydisrupt protein-protein interactions in cancer-related pathways. Moreover, there was a negative correlation between the number of these alternative splicing changes in a sample and the number of somatic mutations in drivers. We propose that a subset of the alternative splicing changes observed in tumors may represent independent oncogenic processes that could be relevant to explain the functional transformations in cancer, and some of them could potentially be considered alternative splicing drivers (AS drivers).
Highlights
Alternative splicing provides the potential to generate diversity at RNA and protein levels from an apparently limited number of loci in the genome (Yang et al, 2016)
Alternative splicing changes may originate from somatic mutations that disrupt splicing regulatory motifs in exons and introns (Jung et al, 2015; Supek et al, 2014), as well as through mutations or expression changes in core and auxiliary splicing factors, which impact the splicing of cancerrelated genes (Bechara et al, 2013; Darman et al, 2015; Madan et al, 2015; Zong et al, 2014)
Patient-Specific Definition of Isoform Switches across Multiple Cancer Types To determine the potential functional impacts of alternative splicing in cancer, we analyzed the expression of human transcript isoforms in 4,542 samples from 11 cancer types from The Cancer Genome Atlas (TCGA) (Supplemental Experimental Procedures)
Summary
Alternative splicing provides the potential to generate diversity at RNA and protein levels from an apparently limited number of loci in the genome (Yang et al, 2016). Many alternative splicing changes recapitulate cancer-associated phenotypes by promoting angiogenesis (Vorlovaet al., 2011), inducing cell proliferation (Yanagisawa et al, 2008), or avoiding apoptosis (Karni et al, 2007). Alterations in alternative splicing are emerging as relevant targets of therapy (Lee and AbdelWahab, 2016). Lung tumors with an exon skipping in the proto-oncogene MET respond to MET-targeted therapies despite not having any other activating alteration in this gene (Frampton et al, 2015; Paik et al, 2015). Specific alterations in splicing induce functional impacts that provide a selective advantage to tumor cells and could represent targets of therapy
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