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    Systematic Analysis of Splice-Site-Creating Mutations in Cancer

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    Author
    Jayasinghe, RG; Cao, S; Gao, Q; Wendl, MC; Vo, NS; Reynolds, SM; Zhao, Y; Climente-Gonzalez, H; Chai, S; Wang, F; ...
    Date
    2018-04-03
    Source Title
    Cell Reports
    Publisher
    CELL PRESS
    Affiliation
    Surgery (RMH)
    Medicine and Radiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Jayasinghe, R. G., Cao, S., Gao, Q., Wendl, M. C., Vo, N. S., Reynolds, S. M., Zhao, Y., Climente-Gonzalez, H., Chai, S., Wang, F., Varghese, R., Huang, M., Liang, W. -W., Wyczalkowski, M. A., Sengupta, S., Li, Z., Payne, S. H., Fenyo, D., Miner, J. H. ,... Ding, L. (2018). Systematic Analysis of Splice-Site-Creating Mutations in Cancer. CELL REPORTS, 23 (1), pp.270-+. https://doi.org/10.1016/j.celrep.2018.03.052.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253736
    DOI
    10.1016/j.celrep.2018.03.052
    Abstract
    For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases.

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