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

Ting-You Wang1, Qi Liu2, Yanan Ren1

  • 1The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.

Molecular Cell
|April 16, 2021
PubMed

Insights

Exitron splicing (EIS) generates protein diversity and is prevalent in 63% of human genes, often promoting cancer progression. EIS-derived neoantigens may predict response to immunotherapy.

Area of Science:

  • Molecular Biology
  • Genomics
  • Cancer Research

Background:

  • Exitron splicing (EIS) is a mechanism that increases proteome diversity by inserting cryptic introns into coding exons.
  • Emerging evidence suggests a potential role for EIS in cancer development and progression.
  • The precise impact and prevalence of EIS in human cancers remain largely uncharacterized.

Purpose of the Study:

  • To systematically investigate the landscape of EIS across a wide range of human cancers.
  • To determine the functional consequences of EIS on cancer driver genes and its potential as a source of neoantigens.
  • To explore the association between EIS-derived neoantigens and clinical outcomes, specifically response to checkpoint inhibitors.

Main Methods:

  • Analysis of 9,599 tumor transcriptomes from 33 distinct cancer types to identify EIS events.
  • Comparative analysis of EIS patterns with somatic mutations in affected genes.
  • Functional assessment of EIS in known and novel cancer driver genes.
  • Identification and characterization of EIS-derived neoepitopes binding to MHC class I and II molecules.
  • Correlation analysis of EIS-derived neoantigen load with checkpoint inhibitor response in a clear cell renal cell carcinoma cohort.

Main Results:

  • EIS affects 63% of human coding genes, with 95% of these events being tumor-specific.
  • A mutually exclusive pattern was observed between EIS and somatic mutations within the same genes.
  • EIS alters cancer driver genes, contributing to gain- or loss-of-function and promoting tumor progression.
  • EIS generates neoepitopes capable of binding to MHC class I and II.
  • Higher EIS-derived neoantigen load is associated with improved response to checkpoint inhibitors in clear cell renal cell carcinoma.

Conclusions:

  • EIS is a widespread and tumor-specific phenomenon significantly contributing to cancer biology.
  • EIS plays a functional role in cancer progression by altering driver genes and generating immunogenic neoepitopes.
  • Considering EIS alterations is crucial for accurate cancer driver event nomination and neoantigen-based immunotherapy strategies.
Keywords:
GTExTCGAcancer driver genescheckpoint inhibition immunotherapyexitronimmunopeptidomeneoantigensnon-canonical splicingpan-cancer analysistranscriptome alterations

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