Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors

Michael B Mumphrey; Noshad Hosseini; Abhijit Parolia; Jie Geng; Weiping Zou; Malini Raghavan; Arul Chinnaiyan; Marcin Cieslik

doi:10.1016/j.celrep.2023.112965

Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors

Cell Rep. 2023 Aug 29;42(8):112965. doi: 10.1016/j.celrep.2023.112965. Epub 2023 Aug 21.

Authors

Michael B Mumphrey¹, Noshad Hosseini¹, Abhijit Parolia², Jie Geng³, Weiping Zou⁴, Malini Raghavan³, Arul Chinnaiyan⁵, Marcin Cieslik⁶

Affiliations

¹ Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA.
⁵ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA.
⁶ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA. Electronic address: mcieslik@med.umich.edu.

PMID: 37597185
DOI: 10.1016/j.celrep.2023.112965

Abstract

Disruption of antigen presentation via loss of major histocompatibility complex (MHC) expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. Here, we develop the personalized genomics algorithm Hapster and accurately call somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1,663 non-synonymous mutations that provide key insights into MHC mutagenesis. We find that MHC class I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC class II mutations are more restricted. Recurrent deleterious mutations are found within haplotype- and cancer-type-specific hotspots associated with distinct mutational processes. Functional classification of MHC residues reveals significant positive selection for mutations disruptive to the B2M, peptide, and T cell binding interfaces, as well as to MHC chaperones.

Keywords: CP: Cancer; CP: Immunology; HLA; MHC; cancer; evolution; genomics; immunogenetics; selection; somatic mutations.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

HLA Antigens
Histocompatibility Antigens Class I* / metabolism
Histocompatibility Antigens Class II / genetics
Humans
Mutation / genetics
Neoplasms* / genetics
T-Lymphocytes

Substances

Histocompatibility Antigens Class I
HLA Antigens
Histocompatibility Antigens Class II

Abstract

Publication types

MeSH terms

Substances

Grants and funding