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Intron retention is a widespread mechanism of tumor-suppressor inactivation

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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Figure 1: Identification of SNVs disrupting splicing.
Figure 2: Positional association of somatic SNVs with abnormal splicing.
Figure 3: Disruption of gene expression by LBEMs.
Figure 4: SNVs disrupting splicing in TSGs.
Figure 5: Characterization of discriminative features for splicing aberration and construction of prediction models.

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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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Authors

Contributions

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.

Corresponding authors

Correspondence to Dongwan Hong, Peter J Park or Eunjung Lee.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–19 and Supplementary Note. (PDF 3178 kb)

Supplementary Tables 1–14

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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