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W. Rathmell
Last active: 11/27/2019

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

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 WW, 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
Cell Rep. 2018 23 (1): 270-281.e3

PMID: 29617666 · PMCID: PMC6055527 · DOI:10.1016/j.celrep.2018.03.052

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.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (11)

BRCA1 Protein GATA3 Transcription Factor HEK293 Cells Humans Mutation Neoplasms Poly (ADP-Ribose) Polymerase-1 Programmed Cell Death 1 Receptor RNA Splice Sites Tumor Suppressor Protein p53 X-linked Nuclear Protein

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