Abstract
A substantial fraction of disease-causing mutations are pathogenic through aberrant splicing. Although genome profiling studies have identified somatic single-nucleotide variants (SNVs) in cancer, the extent to which these variants trigger abnormal splicing has not been systematically examined. Here we analyzed RNA sequencing and exome data from 1,812 patients with cancer and identified ∼900 somatic exonic SNVs that disrupt splicing. At least 163 SNVs, including 31 synonymous ones, were shown to cause intron retention or exon skipping in an allele-specific manner, with ∼70% of the SNVs occurring on the last base of exons. Notably, SNVs causing intron retention were enriched in tumor suppressors, and 97% of these SNVs generated a premature termination codon, leading to loss of function through nonsense-mediated decay or truncated protein. We also characterized the genomic features predictive of such splicing defects. Overall, this work demonstrates that intron retention is a common mechanism of tumor-suppressor inactivation.
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Acknowledgements
We thank S.J. Elledge, H. Schaa, A. Han, N. Gehlenborg and N. Smedemark-Margulies for insightful discussion on tumor-suppressor inactivation, providing a script to determine H-bond scores, advice on minigene experimental validation, comments on visualization, and critical reading and editing of the manuscript, respectively. This study was supported by a grant from the National Cancer Center, Korea (NCC-1310190 and NCC-1410675 to D.H.). E.L. was supported by the Harvard Medical School Eleanor and Miles Shore fellowship and William Randolph Hearst Fund.
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H.J., P.J.P. and E.L. designed the study and analyzed the data. H.J., D.L. and J.L. performed bioinformatics analyses. D.P., Y.K. and W.P. performed minigene experiments. H.J., D.L., P.J.P. and E.L. wrote the manuscript. D.H., P.J.P. and E.L. supervised the project.
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Supplementary Figures 1–19 and Supplementary Note. (PDF 3178 kb)
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Supplementary Tables 1–14. (XLSX 1294 kb)
Supplementary Data Set
Sanger sequence analysis of intron retention–causing LBEMs in TSGs. (ZIP 1277 kb)
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Jung, H., Lee, D., Lee, J. et al. Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat Genet 47, 1242–1248 (2015). https://doi.org/10.1038/ng.3414
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DOI: https://doi.org/10.1038/ng.3414
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