Discovery of driver non-coding splice-site-creating mutations in cancer

Song Cao, Daniel Cui Zhou, Clara Oh, Reyka G. Jayasinghe, Yanyan Zhao, Christopher J. Yoon, Matthew A. Wyczalkowski, Matthew H. Bailey, Terrence Tsou, Qingsong Gao, Andrew Malone, Sheila Reynolds, Ilya Shmulevich, Michael C. Wendl, Feng Chen () and Li Ding ()
Additional contact information
Song Cao: Washington University in St. Louis
Daniel Cui Zhou: Washington University in St. Louis
Clara Oh: Washington University in St. Louis
Reyka G. Jayasinghe: Washington University in St. Louis
Yanyan Zhao: Washington University in St. Louis
Christopher J. Yoon: Washington University in St. Louis
Matthew A. Wyczalkowski: Washington University in St. Louis
Matthew H. Bailey: Washington University in St. Louis
Terrence Tsou: Washington University in St. Louis
Qingsong Gao: Washington University in St. Louis
Andrew Malone: Washington University in St. Louis
Sheila Reynolds: Institute for Systems Biology
Ilya Shmulevich: Institute for Systems Biology
Michael C. Wendl: Washington University in St. Louis
Feng Chen: Washington University in St. Louis
Li Ding: Washington University in St. Louis

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Non-coding mutations can create splice sites, however the true extent of how such somatic non-coding mutations affect RNA splicing are largely unexplored. Here we use the MiSplice pipeline to analyze 783 cancer cases with WGS data and 9494 cases with WES data, discovering 562 non-coding mutations that lead to splicing alterations. Notably, most of these mutations create new exons. Introns associated with new exon creation are significantly larger than the genome-wide average intron size. We find that some mutation-induced splicing alterations are located in genes important in tumorigenesis (ATRX, BCOR, CDKN2B, MAP3K1, MAP3K4, MDM2, SMAD4, STK11, TP53 etc.), often leading to truncated proteins and affecting gene expression. The pattern emerging from these exon-creating mutations suggests that splice sites created by non-coding mutations interact with pre-existing potential splice sites that originally lacked a suitable splicing pair to induce new exon formation. Our study suggests the importance of investigating biological and clinical consequences of noncoding splice-inducing mutations that were previously neglected by conventional annotation pipelines. MiSplice will be useful for automatically annotating the splicing impact of coding and non-coding mutations in future large-scale analyses.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19307-6

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DOI: 10.1038/s41467-020-19307-6

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