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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.
AuthorsHyunchul Jung, Donghoon Lee, Jongkeun Lee, Donghyun Park, Yeon Jeong Kim, Woong-Yang Park, Dongwan Hong, Peter J Park, Eunjung Lee
JournalNature genetics (Nat Genet) Vol. 47 Issue 11 Pg. 1242-8 (Nov 2015) ISSN: 1546-1718 [Electronic] United States
PMID26437032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Codon, Nonsense
  • Tumor Suppressor Proteins
Topics
  • Alternative Splicing
  • Codon, Nonsense (genetics)
  • Exome (genetics)
  • Exons (genetics)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Introns (genetics)
  • Models, Genetic
  • Neoplasms (genetics, pathology)
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, RNA (methods, statistics & numerical data)
  • Tumor Suppressor Proteins (genetics)

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