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Title: Systematic Analysis of Splice-Site-Creating Mutations in Cancer
Authors: JAYASINGHE, Reyka G.CAO, SongGAO, QingsongWENDL, Michael C.VO, Nam SyREYNOLDS, Sheila M.ZHAO, YanyanCLIMENTE-GONZALEZ, HectorCHAI, ShengjieWANG, FangVARGHESE, RajeesHUANG, MoLIANG, Wen-WeiWYCZALKOWSKI, Matthew A.SENGUPTA, SohiniLI, ZhiPAYNE, Samuel H.FENYO, DavidMINER, Jeffrey H.WALTER, Matthew J.VINCENT, BenjaminEYRAS, EduardoCHEN, KenSHMULEVICH, IlyaCHEN, FengDING, Li
Citation: CELL REPORTS, v.23, n.1, p.270-281.e3, 2018
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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Artigos e Materiais de Revistas Científicas - FM/Outros
Outros departamentos - FM/Outros

Artigos e Materiais de Revistas Científicas - IMT
Instituto de Medicina Tropical - IMT

Artigos e Materiais de Revistas Científicas - LIM/14
LIM/14 - Laboratório de Investigação em Patologia Hepática

Artigos e Materiais de Revistas Científicas - ODS/03
ODS/03 - Saúde e bem-estar

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