Systematic analysis of splice-site-creating mutations in cancer

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• dc.contributor.author Jayasinghe, Reyka G.ca
• dc.contributor.author Eyras Jiménez, Eduardoca
• dc.contributor.author Ding, Lica
• dc.contributor.author The Cancer Genome Atlas (TCGA) Research Networkca
• dc.date.accessioned 2018-04-11T07:28:24Z
• dc.date.available 2018-04-11T07:28:24Z
• dc.date.issued 2018
• 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.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.doi http://dx.doi.org/10.1016/j.celrep.2018.03.052
• dc.identifier.issn 2211-1247
• dc.identifier.uri http://hdl.handle.net/10230/34334
• dc.language.iso eng
• dc.publisher Elsevierca
• 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.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Mutations of clinical relevance
• dc.subject.keyword Splicing
• dc.subject.keyword RNA
• dc.title Systematic analysis of splice-site-creating mutations in cancerca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion