Abstract
Exitron splicing (EIS) creates a cryptic intron (called an exitron) within a protein-coding exon to increase proteome diversity. EIS is poorly characterized, but emerging evidence suggests a role for EIS in cancer. Through a systematic investigation of EIS across 33 cancers from 9,599 tumor transcriptomes, we discovered that EIS affected 63% of human coding genes and that 95% of those events were tumor specific. Notably, we observed a mutually exclusive pattern between EIS and somatic mutations in their affected genes. Functionally, we discovered that EIS altered known and novel cancer driver genes for causing gain- or loss-of-function, which promotes tumor progression. Importantly, we identified EIS-derived neoepitopes that bind to major histocompatibility complex (MHC) class I or II. Analysis of clinical data from a clear cell renal cell carcinoma cohort revealed an association between EIS-derived neoantigen load and checkpoint inhibitor response. Our findings establish the importance of considering EIS alterations when nominating cancer driver events and neoantigens.
Original language | English (US) |
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Pages (from-to) | 2246-2260.e12 |
Journal | Molecular Cell |
Volume | 81 |
Issue number | 10 |
DOIs | |
State | Published - May 20 2021 |
Keywords
- GTEx
- TCGA
- cancer driver genes
- checkpoint inhibition immunotherapy
- exitron
- immunopeptidome
- neoantigens
- non-canonical splicing
- pan-cancer analysis
- transcriptome alterations
- Amino Acid Sequence
- Cell Line
- Introns/genetics
- Mutation/genetics
- Humans
- Gene Expression Profiling
- Neoplasms/genetics
- Epitopes/genetics
- RNA Splicing/genetics
- Exons/genetics
- Oncogenes
- Cohort Studies
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology