MHC-I Genotype Restricts the Oncogenic Mutational Landscape

Cell. 2017 Nov 30;171(6):1272-1283.e15. doi: 10.1016/j.cell.2017.09.050. Epub 2017 Oct 26.


MHC-I molecules expose the intracellular protein content on the cell surface, allowing T cells to detect foreign or mutated peptides. The combination of six MHC-I alleles each individual carries defines the sub-peptidome that can be effectively presented. We applied this concept to human cancer, hypothesizing that oncogenic mutations could arise in gaps in personal MHC-I presentation. To validate this hypothesis, we developed and applied a residue-centric patient presentation score to 9,176 cancer patients across 1,018 recurrent oncogenic mutations. We found that patient MHC-I genotype-based scores could predict which mutations were more likely to emerge in their tumor. Accordingly, poor presentation of a mutation across patients was correlated with higher frequency among tumors. These results support that MHC-I genotype-restricted immunoediting during tumor formation shapes the landscape of oncogenic mutations observed in clinically diagnosed tumors and paves the way for predicting personal cancer susceptibilities from knowledge of MHC-I genotype.

Keywords: antigen presentation; cancer; cancer predisposition; cancer susceptibility prediction; human leukocyte antigen; immunoediting; immunology; immunotherapy; major histocompatibility complex; neoantigens.

MeSH terms

  • Antigen Presentation*
  • Cell Line, Tumor
  • Computer Simulation
  • Female
  • HeLa Cells
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Male
  • Monitoring, Immunologic
  • Mutation*
  • Neoplasms / immunology*
  • Proteome


  • Histocompatibility Antigens Class I
  • Proteome