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| Item Type: | Article |
|---|---|
| Title: | MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution |
| Creators Name: | Puttick, C., Jones, T.P., Leung, M.M., Galvez-Cancino, F., Liu, J., Varas-Godoy, M., Rowan, A., Pich, O., Martinez-Ruiz, C., Bentham, R., Dijkstra, K.K., Black, J.R.M., Rosenthal, R., Kanu, N., Litchfield, K., Salgado, R., Moore, D.A., Van Loo, P., Jamal-Hanjani, M., Quezada, S.A., Swanton, C. and McGranahan, N. |
| 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: | Breast Cancer, Genome Informatics, Lung Cancer, Tumour Immunology |
| Source: | Nature Genetics |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Volume: | 56 |
| Number: | 10 |
| Page Range: | 2121-2131 |
| Date: | October 2024 |
| Additional Information: | Tom Kaufmann is a member of TRACERx Consortium |
| Official Publication: | https://doi.org/10.1038/s41588-024-01883-8 |
| PubMed: | View item in PubMed |
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