MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution

Clare Puttick; Thomas P. Jones; Michelle M. Leung; Felipe Galvez-Cancino; Jiali Liu; Manuel Varas-Godoy; Andrew Rowan; Oriol Pich; Carlos Martinez-Ruiz; Robert Bentham; Krijn K. Dijkstra; James R.M. Black; Rachel Rosenthal; Nnennaya Kanu; Kevin Litchfield; Roberto Salgado; David A. Moore; Peter Van Loo; Mariam Jamal-Hanjani; Sergio A. Quezada; Philip Crosbie; Vijay Joshi; Rajesh Shah; Paul Bishop; Leena Joseph; Kendadai Rammohan; Juliette Novasio; Felice Granato; Eustace Fontaine; Elaine Smith; Sarah Danson; Dean A. Fennell; Sean Dulloo; Domenic Marrone; Sridhar Rathinam; Rebecca Boyles; Molly Scotland; Mohamad Tufail; Azmina Sodha-Ramdeen; Apostolos Nakas; Amrita Bajaj; Patricia Georg; Serena Chee; Gary Middleton; Madava Djearaman; Helen Shackleford; Gerald Langman; Mandeesh Sangha; Aya Osman; Yien Ning Sophia Wong; TRACERx Consortium; Hugo J.W.L. Aerts

doi:10.1038/s41588-024-01883-8

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution

Clare Puttick, Thomas P. Jones, Michelle M. Leung, Felipe Galvez-Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Oriol Pich, Carlos Martinez-Ruiz, Robert Bentham, Krijn K. Dijkstra, James R.M. Black, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A. Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A. QuezadaPhilip Crosbie, Vijay Joshi, Rajesh Shah, Paul Bishop, Leena Joseph, Kendadai Rammohan, Juliette Novasio, Felice Granato, Eustace Fontaine, Elaine Smith, Sarah Danson, Dean A. Fennell, Sean Dulloo, Domenic Marrone, Sridhar Rathinam, Rebecca Boyles, Molly Scotland, Mohamad Tufail, Azmina Sodha-Ramdeen, Apostolos Nakas, Amrita Bajaj, Patricia Georg, Serena Chee, Gary Middleton, Madava Djearaman, Helen Shackleford, Gerald Langman, Mandeesh Sangha, Aya Osman, Yien Ning Sophia Wong, TRACERx Consortium, Hugo J.W.L. Aerts

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	2121-2131
Number of pages	11
Journal	Nature Genetics
Volume	56
Issue number	10
Early online date	1 Jan 2024
DOIs	https://doi.org/10.1038/s41588-024-01883-8
Publication status	Published - Oct 2024

Access to Document

10.1038/s41588-024-01883-8Licence: CC BY

Cite this

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., ... Aerts, H. J. W. L. (2024). MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution. Nature Genetics, 56(10), 2121-2131. https://doi.org/10.1038/s41588-024-01883-8

@article{cfdb1063f642476eb12f3088038e580b,

title = "MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution",

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.",

author = "Clare Puttick and Jones, {Thomas P.} and Leung, {Michelle M.} and Felipe Galvez-Cancino and Jiali Liu and Manuel Varas-Godoy and Andrew Rowan and Oriol Pich and Carlos Martinez-Ruiz and Robert Bentham and Dijkstra, {Krijn K.} and Black, {James R.M.} and Rachel Rosenthal and Nnennaya Kanu and Kevin Litchfield and Roberto Salgado and Moore, {David A.} and {Van Loo}, Peter and Mariam Jamal-Hanjani and Quezada, {Sergio A.} and Philip Crosbie and Vijay Joshi and Rajesh Shah and Paul Bishop and Leena Joseph and Kendadai Rammohan and Juliette Novasio and Felice Granato and Eustace Fontaine and Elaine Smith and Sarah Danson and Fennell, {Dean A.} and Sean Dulloo and Domenic Marrone and Sridhar Rathinam and Rebecca Boyles and Molly Scotland and Mohamad Tufail and Azmina Sodha-Ramdeen and Apostolos Nakas and Amrita Bajaj and Patricia Georg and Serena Chee and Gary Middleton and Madava Djearaman and Helen Shackleford and Gerald Langman and Mandeesh Sangha and Aya Osman and Wong, {Yien Ning Sophia} and {TRACERx Consortium} and Aerts, {Hugo J.W.L.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = oct,

doi = "10.1038/s41588-024-01883-8",

language = "English",

volume = "56",

pages = "2121--2131",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

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, Crosbie, P, Joshi, V, Shah, R, Bishop, P, Joseph, L, Rammohan, K, Novasio, J, Granato, F, Fontaine, E, Smith, E, Danson, S, Fennell, DA, Dulloo, S, Marrone, D, Rathinam, S, Boyles, R, Scotland, M, Tufail, M, Sodha-Ramdeen, A, Nakas, A, Bajaj, A, Georg, P, Chee, S, Middleton, G, Djearaman, M, Shackleford, H, Langman, G, Sangha, M, Osman, A, Wong, YNS, TRACERx Consortium & Aerts, HJWL 2024, 'MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution', Nature Genetics, vol. 56, no. 10, pp. 2121-2131. https://doi.org/10.1038/s41588-024-01883-8

TY - JOUR

T1 - MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution

AU - Puttick, Clare

AU - Jones, Thomas P.

AU - Leung, Michelle M.

AU - Galvez-Cancino, Felipe

AU - Liu, Jiali

AU - Varas-Godoy, Manuel

AU - Rowan, Andrew

AU - Pich, Oriol

AU - Martinez-Ruiz, Carlos

AU - Bentham, Robert

AU - Dijkstra, Krijn K.

AU - Black, James R.M.

AU - Rosenthal, Rachel

AU - Kanu, Nnennaya

AU - Litchfield, Kevin

AU - Salgado, Roberto

AU - Moore, David A.

AU - Van Loo, Peter

AU - Jamal-Hanjani, Mariam

AU - Quezada, Sergio A.

AU - Crosbie, Philip

AU - Joshi, Vijay

AU - Shah, Rajesh

AU - Bishop, Paul

AU - Joseph, Leena

AU - Rammohan, Kendadai

AU - Novasio, Juliette

AU - Granato, Felice

AU - Fontaine, Eustace

AU - Smith, Elaine

AU - Danson, Sarah

AU - Fennell, Dean A.

AU - Dulloo, Sean

AU - Marrone, Domenic

AU - Rathinam, Sridhar

AU - Boyles, Rebecca

AU - Scotland, Molly

AU - Tufail, Mohamad

AU - Sodha-Ramdeen, Azmina

AU - Nakas, Apostolos

AU - Bajaj, Amrita

AU - Georg, Patricia

AU - Chee, Serena

AU - Middleton, Gary

AU - Djearaman, Madava

AU - Shackleford, Helen

AU - Langman, Gerald

AU - Sangha, Mandeesh

AU - Osman, Aya

AU - Wong, Yien Ning Sophia

AU - TRACERx Consortium

AU - Aerts, Hugo J.W.L.

PY - 2024/10

Y1 - 2024/10

N2 - 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.

AB - 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.

U2 - 10.1038/s41588-024-01883-8

DO - 10.1038/s41588-024-01883-8

M3 - Article

SN - 1061-4036

VL - 56

SP - 2121

EP - 2131

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution

Abstract

Access to Document

Fingerprint

Cite this