title: 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.
authors.affiliation: Research Institute, National Cancer Center, Gyeonggi-do, South Korea.|Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.|Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, California, USA.
authors.forename: Hyunchul
authors.initials: H
authors.lastname: Jung
authors.affiliation: Research Institute, National Cancer Center, Gyeonggi-do, South Korea.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA.
authors.forename: Donghoon
authors.identifier: http://orcid.org/0000-0003-0453-6059
authors.initials: D
authors.lastname: Lee
authors.affiliation: Research Institute, National Cancer Center, Gyeonggi-do, South Korea.|Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi-do, South Korea.
authors.forename: Jongkeun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.|Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company, Ltd., Seoul, South Korea.
authors.forename: Donghyun
authors.initials: D
authors.lastname: Park
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.|Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company, Ltd., Seoul, South Korea.
authors.forename: Yeon Jeong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.|Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Woong-Yang
authors.identifier: http://orcid.org/0000-0003-4234-0380
authors.initials: WY
authors.lastname: Park
authors.affiliation: Research Institute, National Cancer Center, Gyeonggi-do, South Korea.|Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi-do, South Korea.
authors.forename: Dongwan
authors.identifier: http://orcid.org/0000-0002-7816-1299
authors.initials: D
authors.lastname: Hong
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Peter J
authors.identifier: http://orcid.org/0000-0001-9378-960X
authors.initials: PJ
authors.lastname: Park
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
mesh_terms: D017398:Alternative Splicing; D018389:Codon, Nonsense / Q000235:genetics; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007438:Introns / Q000235:genetics*; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D017423:Sequence Analysis, RNA / Q000379:methods / Q000706:statistics & numerical data; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D025521:Tumor Suppressor Proteins