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
Affiliations
Michael B. Mumphrey
Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
Noshad Hosseini
Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
Abhijit Parolia
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Jie Geng
Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI 48109, USA
Weiping Zou
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
Malini Raghavan
Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI 48109, USA
Arul Chinnaiyan
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
Marcin Cieslik
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; Corresponding author
Summary: 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.
