MHC-I Genotype Restricts the Oncogenic Mutational Landscape

Rachel Marty; Saghar Kaabinejadian; David Rossell; Michael J Slifker; Joris van de Haar; Hatice Billur Engin; Nicola de Prisco; Trey Ideker; William H Hildebrand; Joan Font-Burgada; Hannah Carter

doi:10.1016/j.cell.2017.09.050

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.

Authors

Affiliations

¹ Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA.
² Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
³ Department of Economics & Business, Universitat Pompeu Fabra, 08002 Barcelona, Spain.
⁴ Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
⁵ Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA; Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
⁶ Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA.
⁷ Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
⁸ Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Cancer Cell Map Initiative (CCMI), University of California San Diego, La Jolla, CA 92093, USA; Department of Computer Science, University of California San Diego, La Jolla, CA 92093, USA.
⁹ Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Electronic address: joan.font-burgada@fccc.edu.
¹⁰ Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Cancer Cell Map Initiative (CCMI), University of California San Diego, La Jolla, CA 92093, USA.

Abstract

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

Substances

Histocompatibility Antigens Class I
Proteome

Abstract

MeSH terms

Substances

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