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