Systematic Analysis of Splice-Site-Creating Mutations in Cancer

Grazi GL

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)270-281.e3
JournalCell Reports
Volume23
Issue number1
DOIs
Publication statusPublished - Apr 3 2018
Externally publishedYes

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Tumors
Mutation
Bioelectric potentials
Bioinformatics
Neoplasms
Genes
RNA
DNA
Missense Mutation
Computational Biology
Glioma

Keywords

  • RNA
  • mutations of clinical relevance
  • splicing

Cite this

Systematic Analysis of Splice-Site-Creating Mutations in Cancer. / Grazi GL.

In: Cell Reports, Vol. 23, No. 1, 03.04.2018, p. 270-281.e3.

Research output: Contribution to journalArticle

Grazi GL. / Systematic Analysis of Splice-Site-Creating Mutations in Cancer. In: Cell Reports. 2018 ; Vol. 23, No. 1. pp. 270-281.e3.
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AU - Grazi GL

AU - Jayasinghe, R. G.

AU - Cao, S.

AU - Gao, Q.

AU - Wendl, M. C.

AU - Vo, N. S.

AU - Reynolds, S. M.

AU - Zhao, Y.

AU - Climente-Gonzalez, H.

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AU - Wang, F.

AU - Varghese, R.

AU - Huang, M.

AU - Liang, W. W.

AU - Wyczalkowski, M. A.

AU - Sengupta, S.

AU - Li, Z.

AU - Payne, S. H.

AU - Fenyo, D.

AU - Miner, J. H.

AU - Walter, M. J.

AU - Network, Cancer Genome Atlas Research

AU - Vincent, B.

AU - Eyras, E.

AU - Chen, K.

AU - Shmulevich, I.

AU - Chen, F.

AU - Ding, L.

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N2 - 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.

AB - 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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KW - mutations of clinical relevance

KW - splicing

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