TY - JOUR
T1 - A comprehensive characterization of cis-acting splicing-associated variants in human cancer
AU - Shiraishi, Yuichi
AU - Kataoka, Keisuke
AU - Chiba, Kenichi
AU - Okada, Ai
AU - Kogure, Yasunori
AU - Tanaka, Hiroko
AU - Ogawa, Seishi
AU - Miyano, Satoru
N1 - Funding Information:
This work was supported by Grant-in-Aid from the Japan Agency for Medical Research and Development (Advanced Genome Research and Bioinformatics Study to Facilitate Medical Innovation [17km0405207h0002]), Grant-in-Aid for Scientific Research (KAKENHI 15H05912, 15H05909, and 15K00398), National Cancer Center Research and Development Funds (29-E-3), and Post-K Research and Development (R&D) projects (hp170227). We thank André Kahles, Cameron Soulette, Gunnar Rätsch, Angela Brooks, and PCAWG-3 splicing team members for helpful discussions and feedback on the performance of SAVNet. We thank Naoyuki Kataoka for expert opinion, Miki Sagou for technical assistance, and Yuki Saito for manuscript proofreading. The supercomputing resources were provided by the Human Genome Center, the Institute of Medical Science, The University of Tokyo. The results shown here are partly based upon data generated by TCGA Research Network (http://cancergenome.nih.gov/).
Publisher Copyright:
© 2018 Shiraishi et al.
PY - 2018/8
Y1 - 2018/8
N2 - Although many driver mutations are thought to promote carcinogenesis via abnormal splicing, the landscape of splicing-associated variants (SAVs) remains unknown due to the complexity of splicing abnormalities. Here, we developed a statistical framework to systematically identify SAVs disrupting or newly creating splice site motifs and applied it to matched whole-exome and transcriptome sequencing data from 8976 samples across 31 cancer types, generating a catalog of 14,438 SAVs. Such a large collection of SAVs enabled us to characterize their genomic features, underlying mutational processes, and influence on cancer driver genes. In fact, ∼50% of SAVs identified were those disrupting noncanonical splice sites (non-GT-AG dinucleotides), including the third and fifth intronic bases of donor sites, or newly creating splice sites. Mutation signature analysis revealed that tobacco smoking is more strongly associated with SAVs, whereas ultraviolet exposure has less impact. SAVs showed remarkable enrichment of cancer-related genes, and as many as 14.7% of samples harbored at least one SAVs affecting them, particularly in tumor suppressors. In addition to intron retention, whose association with tumor suppressor inactivation has been previously reported, exon skipping and alternative splice site usage caused by SAVs frequently affected tumor suppressors. Finally, we described high-resolution distributions of SAVs along the gene and their splicing outcomes in commonly disrupted genes, including TP53, PIK3R1, GATA3, and CDKN2A, which offers genetic clues for understanding their functional properties. Collectively, our findings delineate a comprehensive portrait of SAVs, novel insights into transcriptional de-regulation in cancer.
AB - Although many driver mutations are thought to promote carcinogenesis via abnormal splicing, the landscape of splicing-associated variants (SAVs) remains unknown due to the complexity of splicing abnormalities. Here, we developed a statistical framework to systematically identify SAVs disrupting or newly creating splice site motifs and applied it to matched whole-exome and transcriptome sequencing data from 8976 samples across 31 cancer types, generating a catalog of 14,438 SAVs. Such a large collection of SAVs enabled us to characterize their genomic features, underlying mutational processes, and influence on cancer driver genes. In fact, ∼50% of SAVs identified were those disrupting noncanonical splice sites (non-GT-AG dinucleotides), including the third and fifth intronic bases of donor sites, or newly creating splice sites. Mutation signature analysis revealed that tobacco smoking is more strongly associated with SAVs, whereas ultraviolet exposure has less impact. SAVs showed remarkable enrichment of cancer-related genes, and as many as 14.7% of samples harbored at least one SAVs affecting them, particularly in tumor suppressors. In addition to intron retention, whose association with tumor suppressor inactivation has been previously reported, exon skipping and alternative splice site usage caused by SAVs frequently affected tumor suppressors. Finally, we described high-resolution distributions of SAVs along the gene and their splicing outcomes in commonly disrupted genes, including TP53, PIK3R1, GATA3, and CDKN2A, which offers genetic clues for understanding their functional properties. Collectively, our findings delineate a comprehensive portrait of SAVs, novel insights into transcriptional de-regulation in cancer.
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U2 - 10.1101/gr.231951.117
DO - 10.1101/gr.231951.117
M3 - Article
C2 - 30012835
AN - SCOPUS:85050873685
VL - 28
SP - 1111
EP - 1125
JO - Genome Research
JF - Genome Research
SN - 1088-9051
IS - 8
ER -