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Systematic analysis of splice-site-creating mutations in cancer

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dc.contributor.author Jayasinghe, Reyka G.
dc.contributor.author Eyras Jiménez, Eduardo
dc.contributor.author Ding, Li
dc.contributor.author The Cancer Genome Atlas (TCGA) Research Network
dc.date.accessioned 2018-04-11T07:28:24Z
dc.date.available 2018-04-11T07:28:24Z
dc.date.issued 2018
dc.identifier.citation Jayasinghe RG, Cao S, Gao Q, Wendl MC, Vo NS, Reynolds SM et al. Cancer Genome Atlas Research Network. Systematic Analysis of Splice-Site-Creating Mutations in Cancer. Cell Rep. 2018 Apr 3;23(1):270-81.e3. DOI: 10.1016/j.celrep.2018.03.052
dc.identifier.issn 2211-1247
dc.identifier.uri http://hdl.handle.net/10230/34334
dc.description.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.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Reports. 2018 Apr 3;23(1):270-81.e3
dc.rights © 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Systematic analysis of splice-site-creating mutations in cancer
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2018.03.052
dc.subject.keyword Mutations of clinical relevance
dc.subject.keyword Splicing
dc.subject.keyword RNA
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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