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Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes

Subjects

Abstract

Alternative splicing is a widespread process contributing to structural transcript variation and proteome diversity. In cancer, the splicing process is commonly disrupted, resulting in both functional and non-functional end-products. Cancer-specific splicing events are known to contribute to disease progression; however, the dysregulated splicing patterns found on a genome-wide scale have until recently been less well-studied. In this review, we provide an overview of aberrant RNA splicing and its regulation in cancer. We then focus on the executors of the splicing process. Based on a comprehensive catalog of splicing factor encoding genes and analyses of available gene expression and somatic mutation data, we identify cancer-associated patterns of dysregulation. Splicing factor genes are shown to be significantly differentially expressed between cancer and corresponding normal samples, and to have reduced inter-individual expression variation in cancer. Furthermore, we identify enrichment of predicted cancer-critical genes among the splicing factors. In addition to previously described oncogenic splicing factor genes, we propose 24 novel cancer-critical splicing factors predicted from somatic mutations.

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Acknowledgements

This study was supported by the Southern and Eastern Norway Regional Health Authority (Research Grant ‘Genome Medicine of Colorectal Cancer’, project number 2011024), the Norwegian Cancer Society (PR-2007-0166 and PR-2006-0442), the KG Jebsen foundation and the Research Council of Norway through its Centres of Excellence funding scheme (project number 179571).

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Correspondence to R I Skotheim.

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SK is a CEO and Co-Founder of MediSapiens Ltd. AR is employed by MediSapiens Ltd. The remaining authors declare no conflict of interest.

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Sveen, A., Kilpinen, S., Ruusulehto, A. et al. Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes. Oncogene 35, 2413–2427 (2016). https://doi.org/10.1038/onc.2015.318

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