MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution
Authors: 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 R. M. , Rosenthal Rachel , Kanu Nnennaya , Litchfield Kevin , Salgado Roberto , Moore David A. , Van Loo Peter , Jamal-Hanjani Mariam , Quezada Sergio A. ,   TRACERx Consortium, Cheyne Heather , Khalil Mohammed , Richardson Shirley , Cruickshank Tracey , Lim Eric , Aerts Hugo J. W. L. , Kaufmann Tom L. , Huska Matthew R. , Naidu Babu , Wilson Gareth A. , Rosenthal Rachel , Rowan Andrew , Bailey Chris , Lee Claudia , Colliver Emma , Enfield Katey S. S. , Hill Mark S. , Angelova Mihaela , Pich Oriol , Biswas Dhruva , Puttick Clare , Vendramin Roberto , Murphy Cian , Zagorulya Maria , Jones Thomas P. , Leung Michelle M. , McGranahan Nicholas , Castignani Carla , Cadieux Elizabeth Larose , Kittel Jeanette , Haase Kerstin , Koh Kexin , Scott Rachel , Matharu Gurdeep , Shaw Jacqui A. , Hackshaw Allan , Pilotti Camilla , Leslie Rachel , Hacker Anne-Marie , Smith Sean , Walker Aoife , Abbosh Christopher , Richard Corentin , Naceur-Lombardelli Cristina , Gimeno-Valiente Francisco , Thakkar Krupa , Sunderland Mariana Werner , Sivakumar Monica , Kanu Nnennaya , Usaite Ieva , Saghafinia Sadegh , Veeriah Selvaraju , Vanloo Sharon , Mussa Bushra , Magala Michalina , Keene Elizabeth , Lim Emilia L. , Black James R. sM , Bakir Maise Al , Huebner Ariana , Grigoriadis Kristiana , Karasaki Takahiro , Frankell Alexander M. , Hiley Crispin T. , Ward Sophia , Harries Sian , Lucas Olivia , Moore David A. , Birkbak Nicolai J. , Martínez-Ruiz Carlos , Thol Kerstin , Bentham Robert , Liu Wing Kin , Bunkum Abigail , Hessey Sonya , Forster Martin D. , Lee Siow Ming , Jamal-Hanjani Mariam , Karagianni Despoina , Quezada Sergio A. , Bola Supreet Kaur , Litchfield Kevin , Swanton Charles , Le Quesne John , AbdulJabbar Khalid , Veiga Catarina , Zaccaria Simone , Tugwood Jonathan , Dive Caroline , Szallasi Zoltan , Diossy Miklos , Marafioti Teresa , Borg Elaine , Falzon Mary , Khiroya Reena , Van Loo Peter , Peggs Karl S. , Price Gillian , Royle Gary , Collins-Fekete Charles-Antoine , Papadatos-Pastos Dionysis , Wilson James , Ahmad Tanya , Benafif Sarah , Cave Judith , Kerr Keith M. , Watkins Thomas B. K. , Salgado Roberto , Procter Alexander James , Ahmed Asia , Taylor Magali N. , Nair Arjun , Lawrence David , Patrini Davide , Lindsay Colin R. , Blackhall Fiona H. , Summers Yvonne , Krebs Matthew G. , Nye Emma , Stone Richard Kevin , Zhang Hanyun , Nicod Jerome , Kirk Alan , Asif Mo , Bilancia Rocco , Kostoulas Nikos , Whiteley Jennifer , Thomas Mathew , Patel Akshay J. , Chuter David , MacKenzie Mairead , Schwarz Roland F. , Kidd Andrew , Fraioli Francesco , Ashford Paul , Kaplar Zoltan , Demeulemeester Jonas , Wilson Claire , Shackcloth Michael J. , Janes Sam M. , Navani Neal , Thakrar Ricky M. , Leek Angela , Hodgkinson Jack Davies , Totton Nicola , Paiva-Correia Antonio , Beck Stephan , Tanic Miljana , Dick Craig , Robinson Lily , Russell Peter , De Sousa Paulo , Jordan Simon , Rice Alexandra , Raubenheimer Hilgardt , Bhayani Harshil , Ambrose Lyn , Devaraj Anand , Chavan Hemangi , Begum Sofina , Buderi Silviu I. , Kaniu Daniel , Malima Mpho , Booth Sarah , Fernandes Nadia , Shah Pratibha , Proli Chiara , Nicholson Andrew G. , Boleti Ekaterini , Hewish Madeleine , Blyth Kevin G. , Lester Jason F. , Chaturvedi Anshuman , Oliveira Pedro , Brown Katherine D. , Carter Mathew , Magness Alastair , Weeden Clare E. , Grönroos Eva , Goldman Jacki , Escudero Mickael , Hobson Philip , Boeing Stefan , Denner Tamara , Barbè Vittorio , Lu Wei-Ting , Hill William , Naito Yutaka , Ramsden Zoe , Kassiotis George , Noorani Imran , Grapa Anca , Alzetani Aiman , Yuan Yinyin , Pan Xiaoxi , French Jack , Gilbert Kayleigh , Dwornik Angela , Karamani Angeliki , Chain Benny , Pearce David R. , Gálvez-Cancino Felip , Stavrou Georgia , Mastrokalos Gerasimos-Theodoros , Lowe Helen L. , Matos Ignacio Garcia , Reading James L. , Hartley John A. , Selvaraju Kayalvizhi , Chen Kezhong , Ensell Leah , Shah Mansi , Litovchenko Maria , Pawlik Piotr , Gamble Samuel , Ung Seng Kuong Anakin , Spanswick Victoria , Wu Yin , Rane Jayant K. , Al-Sawaf Othman , Chervova Olga , Hoogenboom Emilie Martinoni , Monk Fleur , Holding James W. , Choudhary Junaid , Bhakhri Kunal , Gorman Pat , Stephens Robert C. M. , Pisciella Maria Chiara , Bandula Steve , Wong Yien Ning Sophia , Osman Aya , Sangha Mandeesh , Langman Gerald , Shackleford Helen , Djearaman Madava , Middleton Gary , Chee Serena , Georg Patricia , Bajaj Amrita , Nakas Apostolos , Sodha-Ramdeen Azmina , Tufail Mohamad , Scotland Molly , Boyles Rebecca , Rathinam Sridhar , Marrone Domenic , Dulloo Sean , Fennell Dean A. , Danson Sarah , Smith Elaine , Fontaine Eustace , Granato Felice , Novasio Juliette , Rammohan Kendadai , Joseph Leena , Bishop Paul , Shah Rajesh , Joshi Vijay , Crosbie Philip , Swanton Charles , McGranahan Nicholas 
Published: October 2024

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.