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Published on: March 29, 2019
Intron retention is a widespread mechanism of tumor-suppressor inactivation
Hyunchul Jung1,2,3, Donghoon Lee1,4, Jongkeun Lee1,5
1Research Institute, National Cancer Center, Gyeonggi-do, South Korea.
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.
Insights
Somatic single-nucleotide variants (SNVs) in cancer can disrupt gene splicing, leading to intron retention and exon skipping. This study reveals intron retention as a frequent mechanism for inactivating tumor suppressor genes in cancer.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Aberrant splicing is a significant cause of disease-associated mutations.
- Genome profiling has identified somatic single-nucleotide variants (SNVs) in cancer, but their impact on splicing remains under-examined.
Purpose of the Study:
- To systematically investigate the extent to which somatic SNVs in cancer disrupt RNA splicing.
- To identify genomic features predictive of splicing defects caused by SNVs.
Main Methods:
- Analysis of RNA sequencing and exome data from 1,812 cancer patients.
- Identification and characterization of somatic exonic SNVs affecting splicing.
- Assessment of allele-specific intron retention and exon skipping.
Main Results:
- Approximately 900 somatic exonic SNVs disrupting splicing were identified.
- At least 163 SNVs, including 31 synonymous ones, caused intron retention or exon skipping.
- SNVs leading to intron retention were enriched in tumor suppressors, frequently causing premature termination codons and loss of function.
Conclusions:
- Splicing disruption by SNVs is a common event in cancer.
- Intron retention is a prevalent mechanism for tumor suppressor gene inactivation.
- Understanding SNV-induced splicing defects is crucial for cancer research and therapeutic strategies.
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