Journal
MOLECULAR CELL
Volume 81, Issue 10, Pages 2246-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.03.028
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Funding
- DOD [W81XWH-1-9-10161, W81XWH-17-1-0357, W81XWH-19-1-0563, W81XWH-20-1-0504]
- American Cancer Society [129819-IRG-16-189-58-IRG103, RSG-15-192-01, 129819- IRG-16-189-58-IRG81]
- Prostate Cancer Foundation Young Investigator Award
- PhRMA Foundation Research Starter Grant
- NIH [R01CA208257, P50CA180995, R01CA174777]
- Polsky Urologic Cancer Institute of the Robert H
- Lurie Comprehensive Cancer Center of Northwestern University (Polsky Urologic Cancer Institute Research Award)
- Eagles Telethon Postdoctoral Fellowship
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Exitron splicing (EIS) functions in cancer by affecting 63% of human coding genes, 95% of which are tumor specific. EIS alters cancer driver genes, leading to gain- or loss-of-function, and also produces neoepitopes that bind to MHC class I or II. Analysis of clinical data shows a correlation between EIS-derived neoantigen load and checkpoint inhibitor response in clear cell renal cell carcinoma.
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 check-point inhibitor response. Our findings establish the importance of considering EIS alterations when nominating cancer driver events and neoantigens.
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