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

Ting You Wang, Qi Liu, Yanan Ren, Sk Kayum Alam, Li Wang, Zhu Zhu, Luke H. Hoeppner, Scott M. Dehm, Qi Cao*, Rendong Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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 languageEnglish (US)
Pages (from-to)2246-2260.e12
JournalMolecular cell
Issue number10
StatePublished - May 20 2021


  • GTEx
  • TCGA
  • cancer driver genes
  • checkpoint inhibition immunotherapy
  • exitron
  • immunopeptidome
  • neoantigens
  • non-canonical splicing
  • pan-cancer analysis
  • transcriptome alterations

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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