MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution
Clare Puttick, Thomas P. Jones, Michelle Leung, Felipe Gálvez‐Cancino, Jiali Liu, Manuel Varas‐Godoy, Andrew Rowan, Oriol Pich, Carlos Martínez‐Ruiz, Robert B. Bentham, Krijn K. Dijkstra, James R. Black, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A. Moore, Peter Van Loo, Mariam Jamal‐Hanjani, Sergio A. Quezada, Heather Cheyne, Mohammed Khalil, Shirley Richardson, Tracey Cruickshank, Eric Lim, Hugo J. W. L. Aerts, Tom L. Kaufmann, Matthew R. Huska, Babu Naidu, Gareth A. Wilson, Rachel Rosenthal, Andrew Rowan, Chris Bailey, Claudia Lee, Emma Colliver, Katey S. S. Enfield, Mark S. Hill, Mihaela Angelova, Oriol Pich, Dhruva Biswas, Clare Puttick, Roberto Vendramin, Cian Murphy, Maria Zagorulya, Thomas P. Jones, Michelle M. Leung, Nicholas McGranahan, Carla Castignani, Elizabeth Larose Cadieux, Jeanette Kittel, Kerstin Haase, Kexin Koh, Rachel Scott, Gurdeep Matharu, Jacqui A. Shaw, Allan Hackshaw, Camilla Pilotti, Rachel Leslie, Anne-Marie Hacker, Sean Smith, Aoife Walker, Christopher Abbosh, Corentin Richard, Cristina Naceur-Lombardelli, Francisco Gimeno-Valiente, Krupa Thakkar, Mariana Werner Sunderland, Monica Sivakumar, Nnennaya Kanu, Ieva Usaite, Sadegh Saghafinia, Selvaraju Veeriah, Sharon Vanloo, Bushra Mussa, Michalina Magala, Elizabeth Keene, Emilia L. Lim, James R. sM Black, Maise Al Bakir, Ariana Huebner, Kristiana Grigoriadis, Takahiro Karasaki, Alexander M. Frankell, Crispin T. Hiley, Sophia Ward, Sian Harries, Olivia Lucas, David A. Moore, Nicolai J. Birkbak, Carlos Martínez-Ruiz, Kerstin Thol, Robert Bentham, Wing Kin Liu, Abigail Bunkum, Sonya Hessey, Martin D. Forster, Siow Ming Lee, Mariam Jamal-Hanjani, Despoina Karagianni, Sergio A. Quezada
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.