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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)2246-2260.e12
JournalMolecular Cell
Volume81
Issue number10
DOIs
StatePublished - May 20 2021

Bibliographical note

Funding Information:
We acknowledge the following sources of funding: DOD ( W81XWH-19-1-0161 ), American Cancer Society ( 129819-IRG-16-189-58-IRG103 ), Prostate Cancer Foundation Young Investigator Award and PhRMA Foundation Research Starter Grant to R.Y.; DOD ( W81XWH-17-1-0357 , W81XWH-19-1-0563 , and W81XWH-20-1-0504 ), American Cancer Society ( RSG-15-192-01 ), NIH ( R01CA208257 and Prostate SPORE P50CA180995 DRP ), and Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (Polsky Urologic Cancer Institute Research Award) to Q.C.; NIH ( R01CA174777 ) to S.M.D.; American Cancer Society ( 129819-IRG-16-189-58-IRG81 ) to L.H.H., and Eagles Telethon Postdoctoral Fellowship to T.-Y.W. and S.K.A.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

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

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