Skip to main content

Systematic Analysis of Splice-Site-Creating Mutations in Cancer.

Publication ,  Journal Article
Jayasinghe, RG; Cao, S; Gao, Q; Wendl, MC; Vo, NS; Reynolds, SM; Zhao, Y; Climente-González, H; Chai, S; Wang, F; Varghese, R; Huang, M ...
Published in: Cell Rep
April 3, 2018

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

April 3, 2018

Volume

23

Issue

1

Start / End Page

270 / 281.e3

Location

United States

Related Subject Headings

  • X-linked Nuclear Protein
  • Tumor Suppressor Protein p53
  • RNA Splice Sites
  • Programmed Cell Death 1 Receptor
  • Poly (ADP-Ribose) Polymerase-1
  • Neoplasms
  • Mutation
  • Humans
  • HEK293 Cells
  • GATA3 Transcription Factor
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Jayasinghe, R. G., Cao, S., Gao, Q., Wendl, M. C., Vo, N. S., Reynolds, S. M., … Ding, L. (2018). Systematic Analysis of Splice-Site-Creating Mutations in Cancer. Cell Rep, 23(1), 270-281.e3. https://doi.org/10.1016/j.celrep.2018.03.052
Jayasinghe, Reyka G., Song Cao, Qingsong Gao, Michael C. Wendl, Nam Sy Vo, Sheila M. Reynolds, Yanyan Zhao, et al. “Systematic Analysis of Splice-Site-Creating Mutations in Cancer.Cell Rep 23, no. 1 (April 3, 2018): 270-281.e3. https://doi.org/10.1016/j.celrep.2018.03.052.
Jayasinghe RG, Cao S, Gao Q, Wendl MC, Vo NS, Reynolds SM, et al. Systematic Analysis of Splice-Site-Creating Mutations in Cancer. Cell Rep. 2018 Apr 3;23(1):270-281.e3.
Jayasinghe, Reyka G., et al. “Systematic Analysis of Splice-Site-Creating Mutations in Cancer.Cell Rep, vol. 23, no. 1, Apr. 2018, pp. 270-281.e3. Pubmed, doi:10.1016/j.celrep.2018.03.052.
Jayasinghe RG, Cao S, Gao Q, Wendl MC, Vo NS, Reynolds SM, Zhao Y, Climente-González H, Chai S, Wang F, Varghese R, Huang M, Liang W-W, Wyczalkowski MA, Sengupta S, Li Z, Payne SH, Fenyö D, Miner JH, Walter MJ, Cancer Genome Atlas Research Network, Vincent B, Eyras E, Chen K, Shmulevich I, Chen F, Ding L. Systematic Analysis of Splice-Site-Creating Mutations in Cancer. Cell Rep. 2018 Apr 3;23(1):270-281.e3.

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

April 3, 2018

Volume

23

Issue

1

Start / End Page

270 / 281.e3

Location

United States

Related Subject Headings

  • X-linked Nuclear Protein
  • Tumor Suppressor Protein p53
  • RNA Splice Sites
  • Programmed Cell Death 1 Receptor
  • Poly (ADP-Ribose) Polymerase-1
  • Neoplasms
  • Mutation
  • Humans
  • HEK293 Cells
  • GATA3 Transcription Factor