TY  - JOUR
PB  - NATURE PORTFOLIO
ID  - discovery10205080
N2  - 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.
EP  - 2131
AV  - public
Y1  - 2024/10//
TI  - MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution
A1  - Puttick, Clare
A1  - Jones, Thomas P
A1  - Leung, Michelle M
A1  - Galvez-Cancino, Felipe
A1  - Liu, Jiali
A1  - Varas-Godoy, Manuel
A1  - Rowan, Andrew
A1  - Pich, Oriol
A1  - Martinez-Ruiz, Carlos
A1  - Bentham, Robert
A1  - Dijkstra, Krijn K
A1  - Black, James RM
A1  - Rosenthal, Rachel
A1  - Kanu, Nnennaya
A1  - Litchfield, Kevin
A1  - Salgado, Roberto
A1  - Moore, David A
A1  - Van Loo, Peter
A1  - Jamal-Hanjani, Mariam
A1  - Quezada, Sergio A
A1  - Swanton, Charles
A1  - Mcgranahan, Nicholas
JF  - Nature Genetics
SN  - 1061-4036
UR  - https://doi.org/10.1038/s41588-024-01883-8
N1  - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article?s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article?s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
IS  - 10
VL  - 56
SP  - 2121
ER  -