MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution
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 iden...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Nature Research
2024
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| _version_ | 1817931243276206080 |
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| author | Puttick, C Jones, TP Leung, MM Galvez-Cancino, F Liu, J Varas-Godoy, M Rowan, A Pich, O Martinez-Ruiz, C Bentham, R Dijkstra, KK Black, JRM Rosenthal, R Kanu, N Litchfield, K Salgado, R Moore, DA Van Loo, P Jamal-Hanjani, M Quezada, SA Swanton, C McGranahan, N |
| author_facet | Puttick, C Jones, TP Leung, MM Galvez-Cancino, F Liu, J Varas-Godoy, M Rowan, A Pich, O Martinez-Ruiz, C Bentham, R Dijkstra, KK Black, JRM Rosenthal, R Kanu, N Litchfield, K Salgado, R Moore, DA Van Loo, P Jamal-Hanjani, M Quezada, SA Swanton, C McGranahan, N |
| author_sort | Puttick, C |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-12-09T03:18:55Z |
| format | Journal article |
| id | oxford-uuid:a161512c-82c7-43ac-9b77-31173228d861 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:18:55Z |
| publishDate | 2024 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:a161512c-82c7-43ac-9b77-31173228d8612024-10-30T20:13:39ZMHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolutionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a161512c-82c7-43ac-9b77-31173228d861EnglishJisc Publications RouterNature Research2024Puttick, CJones, TPLeung, MMGalvez-Cancino, FLiu, JVaras-Godoy, MRowan, APich, OMartinez-Ruiz, CBentham, RDijkstra, KKBlack, JRMRosenthal, RKanu, NLitchfield, KSalgado, RMoore, DAVan Loo, PJamal-Hanjani, MQuezada, SASwanton, CMcGranahan, NDisruption 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. |
| spellingShingle | Puttick, C Jones, TP Leung, MM Galvez-Cancino, F Liu, J Varas-Godoy, M Rowan, A Pich, O Martinez-Ruiz, C Bentham, R Dijkstra, KK Black, JRM Rosenthal, R Kanu, N Litchfield, K Salgado, R Moore, DA Van Loo, P Jamal-Hanjani, M Quezada, SA Swanton, C McGranahan, N MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution |
| title | MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution |
| title_full | MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution |
| title_fullStr | MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution |
| title_full_unstemmed | MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution |
| title_short | MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution |
| title_sort | mhc hammer reveals genetic and non genetic hla disruption in cancer evolution |
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