RT Journal Article
SR Electronic
T1 Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.22.523447
DO 10.1101/2023.01.22.523447
A1 Michael B. Mumphrey
A1 Noshad Hosseini
A1 Abhijit Parolia
A1 Jie Geng
A1 Weiping Zou
A1 Malini Raghavan
A1 Arul Chinnaiyan
A1 Marcin Cieslik
YR 2023
UL http://biorxiv.org/content/early/2023/01/22/2023.01.22.523447.abstract
AB Disruption of antigen presentation via loss of MHC expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. We developed the personalized genomics algorithm Hapster and accurately called somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1663 nonsynonymous mutations that provide key insights into MHC mutagenesis. We found that MHC-I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC-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 revealed significant positive selection for mutations disruptive to the B2M, peptide, and T-cell binding interfaces, as well as MHC chaperones. At the cohort level, all cancers with positive selection for MHC mutations are responsive to immune checkpoint inhibitors, underscoring the translational relevance of our findings.Competing Interest StatementThe authors have declared no competing interest.