MHC Hammer Reveals Genetic and Non-genetic HLA Disruption in Cancer Evolution

Overview

Journal Nat Genet

Specialty Genetics

Date 2024 Oct 2

PMID 39358601

Authors

Clare Puttick

Thomas P Jones

Michelle M Leung

Felipe Galvez-Cancino

Jiali Liu

Manuel Varas-Godoy

Andrew Rowan

Oriol Pich

Carlos Martinez-Ruiz

Robert Bentham

Krijn K Dijkstra

James R M Black

Rachel Rosenthal

Nnennaya Kanu

Kevin Litchfield

Roberto Salgado

David A Moore

Peter Van Loo

Mariam Jamal-Hanjani

Sergio A Quezada

Charles Swanton

Nicholas McGranahan

Affiliations

Soon will be listed here.

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.

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