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Title: Systematic Analysis of Splice-Site-Creating Mutations in Cancer

Journal Article · · Cell Reports
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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. Finally, our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases.

Research Organization:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Organization:
USDOE
Contributing Organization:
The Cancer Genome Atlas Research Network
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
1433509
Report Number(s):
PNNL-SA-135533; PII: S2211124718303978
Journal Information:
Cell Reports, Vol. 23, Issue 1; ISSN 2211-1247
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 126 works
Citation information provided by
Web of Science

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A Second Leaky Splice-Site Mutation in the Spastin Gene
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journal December 2001
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Cited By (21)

Proteogenomic Analysis of Protein Sequence Alterations in Breast Cancer Cells journal July 2019
Alternative mRNA splicing in cancer immunotherapy journal July 2019
Proneural and mesenchymal glioma stem cells display major differences in splicing and lncRNA profiles journal January 2020
Putatively cancer-specific exon–exon junctions are shared across patients and present in developmental and other non-cancer cells journal January 2020
SpliceHetero: An information theoretic approach for measuring spliceomic intratumor heterogeneity from bulk tumor RNA-seq journal October 2019
An atlas of transposable element-derived alternative splicing in cancer journal February 2020
K120R mutation inactivates p53 by creating an aberrant splice site leading to nonsense-mediated mRNA decay journal October 2018
Pan-cancer analysis of clinical relevance of alternative splicing events in 31 human cancers journal August 2019
Splicing and cancer: Challenges and opportunities journal February 2019
Splicing isoform-specific functional genomic in cancer cells journal December 2018
Alternative tumour-specific antigens journal July 2019
Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide journal December 2018
Finding Neo (antigens, that is) journal July 2019
A deep neural network approach to predicting clinical outcomes of neuroblastoma patients journal December 2019
Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease journal April 2019
Pan-cancer repository of validated natural and cryptic mRNA splicing mutations journal January 2018
A pan-cancer analysis of synonymous mutations journal June 2019
Targeting mRNA processing as an anticancer strategy journal September 2019
Best practices for bioinformatic characterization of neoantigens for clinical utility journal August 2019
Pvclust: an R package for assessing the uncertainty in hierarchical clustering journal April 2006
Pan-cancer repository of validated natural and cryptic mRNA splicing mutations journal January 2018

Figures / Tables (7)

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
splicing
RNA
mutations of clinical relevance