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BMC Med Genomics. 2019 Jul 25;12(Suppl 6):107. doi: 10.1186/s12920-019-0544-1.

Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes.

Castro A1,2, Ozturk K1,2, Pyke RM1,2, Xian S1, Zanetti M3,4, Carter H5,6,7,8.

Author information

1
Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA, 92093, USA.
2
Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA, 92093, USA.
3
Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA.
4
The Laboratory of Immunology and Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
5
Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA, 92093, USA. hkcarter@ucsd.edu.
6
Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA, 92093, USA. hkcarter@ucsd.edu.
7
Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA. hkcarter@ucsd.edu.
8
CIFAR, MaRS Centre, West Tower, 661 University Ave., Suite 505, Toronto, ON, M5G 1M1, Canada. hkcarter@ucsd.edu.

Abstract

BACKGROUND:

The major histocompatibility complex class I (MHC-I) molecule is a protein complex that displays intracellular peptides to T cells, allowing the immune system to recognize and destroy infected or cancerous cells. MHC-I is composed of a highly polymorphic HLA-encoded alpha chain that binds the peptide and a Beta-2-microglobulin (B2M) protein that acts as a stabilizing scaffold. HLA mutations have been implicated as a mechanism of immune evasion during tumorigenesis, and B2M is considered a tumor suppressor gene. However, the implications of somatic HLA and B2M mutations have not been fully explored in the context of antigen presentation via the MHC-I molecule during tumor development. To understand the effect that B2M and HLA MHC-I molecule mutations have on mutagenesis, we analyzed the accumulation of mutations in patients from The Cancer Genome Atlas according to their MHC-I molecule mutation status.

RESULTS:

Somatic B2M and HLA mutations in microsatellite stable tumors were associated with higher overall mutation burden and a larger fraction of HLA-binding neoantigens when compared to B2M and HLA wild type tumors. B2M and HLA mutations were highly enriched in patients with microsatellite instability. B2M mutations tended to occur relatively early during patients' respective tumor development, whereas HLA mutations were either early or late events. In addition, B2M and HLA mutated patients had higher levels of immune infiltration by natural killer and CD8+ T cells and higher levels of cytotoxicity.

CONCLUSIONS:

Our findings add to a growing body of evidence that somatic B2M and HLA mutations are a mechanism of immune evasion by demonstrating that such mutations are associated with a higher load of neoantigens that should be presented via MHC-I.

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