Hyunchul Jung1-3, Donghoon Lee1,4, Jongkeun Lee1,5, Donghyun Park2,6, Yeon Jeong Kim2,6, Woong-Yang Park2,7, Dongwan Hong1,5, Peter J Park8,9 & Eunjung Lee8
1Research Institute, National Cancer Center, Gyeonggi-do, South Korea. 2Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. 3Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, California, USA. 4Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA. 5Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi-do, South Korea. 6Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company, Ltd., Seoul, South Korea. 7Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea. 8Department of Medicine, Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts, USA. 9Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
Correspondence to : Eunjung Lee or Peter J Park or Dongwan Hong
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.