Faculty, Staff and Student Publications
Publication Date
10-1-2024
Journal
Nature Genetics
Abstract
Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.
Keywords
Female, Humans, Adenocarcinoma of Lung, Alleles, Alternative Splicing, Breast Neoplasms, Carcinoma, Squamous Cell, Evolution, Molecular, Gene Expression Regulation, Neoplastic, Histocompatibility Antigens Class I, HLA Antigens, Loss of Heterozygosity, Lung Neoplasms, Major Histocompatibility Complex, Mutation, Neoplasms
DOI
10.1038/s41588-024-01883-8
PMID
39358601
PMCID
PMC11525181
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
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Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons