Hyunchul Jung^1-3, Donghoon Lee^1,4, Jongkeun Lee^1,5, Donghyun Park^2,6, Yeon Jeong Kim^2,6, Woong-Yang Park^2,7, Dongwan Hong^1,5, Peter J Park^8,9 & 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

 

Abstract

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.