Cell
Volume 171, Issue 6, 30 November 2017, Pages 1272-1283.e15
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Article
MHC-I Genotype Restricts the Oncogenic Mutational Landscape

https://doi.org/10.1016/j.cell.2017.09.050Get rights and content
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Highlights

  • Development of a residue-centric patient MHC-I presentation score validated by MS

  • MHC-I genotype is associated with the appearance of specific oncogenic mutations

  • Oncogenic mutation frequency negatively correlates with population MHC-I presentation

  • Recurrent oncogenic mutations are biased toward peptides that are poorly presented

Summary

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

cancer predisposition
cancer susceptibility prediction
major histocompatibility complex
human leukocyte antigen
antigen presentation
cancer
immunology
immunoediting
immunotherapy
neoantigens

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These authors contributed equally

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