eprintid: 10205080 rev_number: 7 eprint_status: archive userid: 699 dir: disk0/10/20/50/80 datestamp: 2025-02-21 12:52:00 lastmod: 2025-02-21 12:52:00 status_changed: 2025-02-21 12:52:00 type: article metadata_visibility: show sword_depositor: 699 creators_name: Puttick, Clare creators_name: Jones, Thomas P creators_name: Leung, Michelle M creators_name: Galvez-Cancino, Felipe creators_name: Liu, Jiali creators_name: Varas-Godoy, Manuel creators_name: Rowan, Andrew creators_name: Pich, Oriol creators_name: Martinez-Ruiz, Carlos creators_name: Bentham, Robert creators_name: Dijkstra, Krijn K creators_name: Black, James RM creators_name: Rosenthal, Rachel creators_name: Kanu, Nnennaya creators_name: Litchfield, Kevin creators_name: Salgado, Roberto creators_name: Moore, David A creators_name: Van Loo, Peter creators_name: Jamal-Hanjani, Mariam creators_name: Quezada, Sergio A creators_name: Swanton, Charles creators_name: Mcgranahan, Nicholas title: MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution ispublished: pub divisions: UCL divisions: B02 divisions: B04 divisions: C10 divisions: D19 divisions: D15 divisions: D17 divisions: D12 divisions: F42 divisions: H01 divisions: G96 divisions: G98 divisions: G99 divisions: G97 divisions: K71 divisions: G19 note: 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/. 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. date: 2024-10 date_type: published publisher: NATURE PORTFOLIO official_url: https://doi.org/10.1038/s41588-024-01883-8 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2324764 doi: 10.1038/s41588-024-01883-8 medium: Print-Electronic pii: 10.1038/s41588-024-01883-8 lyricists_name: Jones, Thomas lyricists_name: Swanton, Robert lyricists_name: Kanu, Nnennaya lyricists_name: McGranahan, Nicholas lyricists_name: Quezada, Sergio lyricists_name: Jamal-Hanjani, Mariam lyricists_name: Moore, David lyricists_name: Black, James lyricists_name: Litchfield, Kevin lyricists_name: Spanswick, Victoria lyricists_name: Chain, Benjamin lyricists_name: Hartley, John lyricists_name: Chervova, Olga lyricists_name: Lowe, Helen lyricists_name: Bentham, Robert lyricists_name: Ensell, Leah lyricists_name: Reading, James lyricists_name: Karamani, Angeliki lyricists_name: Shah, Mansi lyricists_name: Rane, Jayant Kashinath lyricists_name: Royle, Gary lyricists_name: Forster, Martin lyricists_name: Veeriah, Selvaraju lyricists_name: Hackshaw, Allan lyricists_name: Fraioli, Francesco lyricists_name: Janes, Samuel lyricists_name: Tanic, Miljana lyricists_name: Marafioti, Teresa lyricists_name: Vendramin, Roberto lyricists_id: TPJON58 lyricists_id: CSWAN79 lyricists_id: NKANU55 lyricists_id: NLMCG29 lyricists_id: SAQUE92 lyricists_id: MJAMA72 lyricists_id: DMOOR09 lyricists_id: JBLAC10 lyricists_id: KLITC91 lyricists_id: VSPAN04 lyricists_id: BMCHA43 lyricists_id: JAHAR07 lyricists_id: OCHER42 lyricists_id: HIRWI65 lyricists_id: BENTH62 lyricists_id: LENSE54 lyricists_id: JREAD01 lyricists_id: AKARB16 lyricists_id: MSHAC75 lyricists_id: JRANE47 lyricists_id: GROYL68 lyricists_id: MFORS50 lyricists_id: RVEER62 lyricists_id: AHACK11 lyricists_id: FFRAI74 lyricists_id: SMJAN15 lyricists_id: MTANI82 lyricists_id: TMARI28 lyricists_id: RVEND90 actors_name: Hackshaw, Allan actors_id: AHACK11 actors_role: owner funding_acknowledgements: [Common Fund of the Office of the Director of the National Institutes of Health]; [NCI]; [NHGRI]; [NHLBI]; [NIDA]; [NIMH]; [NINDS]; UCL/12/0279 [University College London]; C11496/A17786 [Cancer Research UK]; C444/A15953 [CRUK]; CC2041 [Francis Crick Institute from Cancer Research UK]; CC2041 [UK Medical Research Council]; CC2041 [Wellcome Trust]; [Cancer Research UK Lung Cancer Centre of Excellence]; C7893/A26233 [CRUK City of London Centre Award]; [UCL Experimental Cancer Medicine Centre]; BCRF 23-157 [Breast Cancer Research Foundation]; M630 [Rosetrees Trust]; A28592 [Cancer Research UK Brain Tumor Award]; [Wellcome Trust]; 101024529 [European Union]; 20-45200-98-20102 [ZonMW Rubicon fellowship]; BCRF 23-157 [Breast Cancer Research Foundation]; 101024529 [Marie Curie Actions (MSCA)] full_text_status: public publication: Nature Genetics volume: 56 number: 10 pagerange: 2121-2131 pages: 28 event_location: United States issn: 1061-4036 citation: Puttick, Clare; Jones, Thomas P; Leung, Michelle M; Galvez-Cancino, Felipe; Liu, Jiali; Varas-Godoy, Manuel; Rowan, Andrew; ... Mcgranahan, Nicholas; + view all <#> Puttick, Clare; Jones, Thomas P; Leung, Michelle M; Galvez-Cancino, Felipe; Liu, Jiali; Varas-Godoy, Manuel; Rowan, Andrew; Pich, Oriol; Martinez-Ruiz, Carlos; Bentham, Robert; Dijkstra, Krijn K; Black, James RM; Rosenthal, Rachel; Kanu, Nnennaya; Litchfield, Kevin; Salgado, Roberto; Moore, David A; Van Loo, Peter; Jamal-Hanjani, Mariam; Quezada, Sergio A; Swanton, Charles; Mcgranahan, Nicholas; - view fewer <#> (2024) MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution. Nature Genetics , 56 (10) pp. 2121-2131. 10.1038/s41588-024-01883-8 <https://doi.org/10.1038/s41588-024-01883-8>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10205080/1/MHC%20Hammer%20reveals%20genetic%20and%20non-genetic%20HLA%20disruption%20in%20cancer%20evolution.pdf