A pan-cancer transcriptome analysis of exitron splicing identifies novel cancer driver genes and neoepitopes

Published: 5 January 2021| Version 1 | DOI: 10.17632/vdkpfzjjvg.1
Ting-You Wang


An exitron is a cryptic intron within a protein-coding exon that, when spliced, alters the protein-coding potential of the transcript. Exitrons are poorly characterized, but emerging evidence suggests a role for exitron splicing (EIS) in cancer. Through a systematic investigation of EIS across 33 cancers from 9,599 tumor transcriptomes, we discovered EIS affected over 60% of human coding genes and 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 known and novel cancer driver genes were affected through gain- or loss-of-function EIS alterations to dictate cancer progression. Importantly, we identified EIS-derived neoepitopes that bind to MHC class I and II. Analysis of clinical data from a clear cell renal cell carcinoma cohort revealed EIS-derived neoantigen burden to be significantly associated with checkpoint inhibitor response. Our findings establish the importance of considering EIS alterations when nominating cancer driver events and neoantigens.



University of Minnesota Hormel Institute