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Quantifying immune-based counterselection of somatic mutations.

Fan Yang1,2,3, Dae-Kyum Kim1,2,3, Hidewaki Nakagawa4

  • 1Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

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|July 26, 2019
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Summary
This summary is machine-generated.

Cancer neoantigens generated by somatic mutations are depleted due to immune counterselection. This depletion varies with gene expression and major histocompatibility complex (MHC) allele dominance, offering insights into cancer immunity.

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Area of Science:

  • Immunology
  • Cancer Biology
  • Genetics

Background:

  • Somatic mutations in cancer can create neoantigens, which are recognized by the immune system.
  • The immune system's ability to eliminate cancers via neoantigen recognition (immune counterselection) is crucial but not fully quantified.
  • Previous studies lacked quantitative estimates for the strength of this neoantigen counterselection phenomenon.

Purpose of the Study:

  • To quantify the extent of somatic mutation depletion in peptides presented by major histocompatibility complex (MHC) class I molecules.
  • To investigate factors influencing neoantigen counterselection, including gene expression levels and MHC allele status.
  • To provide a quantitative understanding of counterselection for specific subclasses of neoantigenic somatic variations.

Main Methods:

  • Computational prediction of peptides displayed by MHC class I proteins.
  • Analysis of somatic mutation data in relation to predicted peptide presentation.
  • Statistical assessment of mutation depletion based on gene expression and MHC-encoding allele presence.

Main Results:

  • Somatic mutations were significantly depleted in peptides predicted for MHC class I presentation.
  • The degree of mutation depletion correlated with the expression level of the neoantigenic gene.
  • Depletion was influenced by the number of MHC-encoding alleles capable of presenting the peptide, suggesting incomplete dominance.

Conclusions:

  • This study quantifies the immune counterselection of neoantigens, demonstrating a significant depletion of somatic mutations in presented peptides.
  • Neoantigen gene expression levels and MHC allele characteristics modulate the strength of immune counterselection.
  • The findings offer a foundational quantitative framework for understanding the counterselection of specific neoantigen subclasses in cancer development.