Systematic Analysis of Splice-Site-Creating Mutations in Cancer
Copyright policy )Systematic Analysis of Splice-Site-Creating Mutations in Cancer
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.
- PSL Research University France
- Pacific Northwest National Laboratory United States
- Institiute for Systems Biology United States
- University of Mary United States
- University of North Carolina at Chapel Hill United States
Medical Physiology, Programmed Cell Death 1 Receptor, Poly (ADP-Ribose) Polymerase-1, Cancer Genome Atlas Research Network, Splicing, Inactivation, GENETIC-VARIANTS, Neoplasms, 2.1 Biological and endogenous factors, Biology (General), Cancer, RNA; mutations of clinical relevance; splicing, BRCA1 Protein, Retinoblastoma, Mutations of clinical relevance, Biological Sciences, Biological sciences, 5.1 Pharmaceuticals, Aberrant, INACTIVATION, Immunotherapy, MESSENGER-RNA, Life Sciences & Biomedicine, X-linked Nuclear Protein, QH301-705.5, RETINOBLASTOMA, Bioinformatics and Computational Biology, 610, 610 Medicine & health, GATA3 Transcription Factor, SYNONYMOUS MUTATIONS, Article, splicing, Messenger-Rna, Cancer Genomics, Rare Diseases, 616, Genetics, UNCLASSIFIED VARIANTS, BREAST-CANCER, Humans, Reporter Minigene, Breast-Cancer, TRANSCRIPTOME, Synonymous Mutations, Science & Technology, REPORTER MINIGENE, Human Genome, Unclassified Variants, Cell Biology, ABERRANT, mutations of clinical relevance, HEK293 Cells, Mutation, Genetic-Variants, RNA, Biochemistry and Cell Biology, RNA Splice Sites, Tumor Suppressor Protein p53, Transcriptome, mutations of clinical relevance; RNA; splicing; Biochemistry, Genetics and Molecular Biology (all)
Medical Physiology, Programmed Cell Death 1 Receptor, Poly (ADP-Ribose) Polymerase-1, Cancer Genome Atlas Research Network, Splicing, Inactivation, GENETIC-VARIANTS, Neoplasms, 2.1 Biological and endogenous factors, Biology (General), Cancer, RNA; mutations of clinical relevance; splicing, BRCA1 Protein, Retinoblastoma, Mutations of clinical relevance, Biological Sciences, Biological sciences, 5.1 Pharmaceuticals, Aberrant, INACTIVATION, Immunotherapy, MESSENGER-RNA, Life Sciences & Biomedicine, X-linked Nuclear Protein, QH301-705.5, RETINOBLASTOMA, Bioinformatics and Computational Biology, 610, 610 Medicine & health, GATA3 Transcription Factor, SYNONYMOUS MUTATIONS, Article, splicing, Messenger-Rna, Cancer Genomics, Rare Diseases, 616, Genetics, UNCLASSIFIED VARIANTS, BREAST-CANCER, Humans, Reporter Minigene, Breast-Cancer, TRANSCRIPTOME, Synonymous Mutations, Science & Technology, REPORTER MINIGENE, Human Genome, Unclassified Variants, Cell Biology, ABERRANT, mutations of clinical relevance, HEK293 Cells, Mutation, Genetic-Variants, RNA, Biochemistry and Cell Biology, RNA Splice Sites, Tumor Suppressor Protein p53, Transcriptome, mutations of clinical relevance; RNA; splicing; Biochemistry, Genetics and Molecular Biology (all)
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