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.

Systematic Analysis of Splice-Site-Creating Mutations in Cancer / Reyka G, Jayasinghe; Song, Cao; Qingsong, Gao; Michael C, Wendl; Nam Sy, Vo; Sheila M, Reynolds; Yanyan, Zhao; Héctor, Climente-González; Shengjie, Chai; Fang, Wang; Rajees, Varghese; Mo, Huang; Wen-Wei, Liang; Matthew A, Wyczalkowski; Sohini, Sengupta; Zhi, Li; Samuel H, Payne; David, Fenyö; Jeffrey H, Miner; Matthew J, Walter; Alvaro, Domenico; Bragazzi, MARIA CONSIGLIA; Cardinale, Vincenzo; Gaudio, Eugenio; Benjamin, Vincent; Eduardo, Eyras; Ken, Chen; Ilya, Shmulevich; Feng, Chen; Li, Ding. - In: CELL REPORTS. - ISSN 2211-1247. - 23:1(2018), pp. 270-281.e3-281.e3. [10.1016/j.celrep.2018.03.052]

Systematic Analysis of Splice-Site-Creating Mutations in Cancer

Domenico, Alvaro;Maria C. , Bragazzi;Vincenzo, Cardinale;Eugenio, Gaudio;
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.
2018
RNA; mutations of clinical relevance; splicing
01 Pubblicazione su rivista::01a Articolo in rivista
Systematic Analysis of Splice-Site-Creating Mutations in Cancer / Reyka G, Jayasinghe; Song, Cao; Qingsong, Gao; Michael C, Wendl; Nam Sy, Vo; Sheila M, Reynolds; Yanyan, Zhao; Héctor, Climente-González; Shengjie, Chai; Fang, Wang; Rajees, Varghese; Mo, Huang; Wen-Wei, Liang; Matthew A, Wyczalkowski; Sohini, Sengupta; Zhi, Li; Samuel H, Payne; David, Fenyö; Jeffrey H, Miner; Matthew J, Walter; Alvaro, Domenico; Bragazzi, MARIA CONSIGLIA; Cardinale, Vincenzo; Gaudio, Eugenio; Benjamin, Vincent; Eduardo, Eyras; Ken, Chen; Ilya, Shmulevich; Feng, Chen; Li, Ding. - In: CELL REPORTS. - ISSN 2211-1247. - 23:1(2018), pp. 270-281.e3-281.e3. [10.1016/j.celrep.2018.03.052]
File allegati a questo prodotto
File Dimensione Formato  
Jayasinghe_analysis-splice_2018.pdf

accesso aperto

Tipologia: Documento in Post-print (versione successiva alla peer review e accettata per la pubblicazione)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 2.71 MB
Formato Adobe PDF
2.71 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1106361
Citazioni
  • ???jsp.display-item.citation.pmc??? 81
  • Scopus 153
  • ???jsp.display-item.citation.isi??? 140
social impact