DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load

Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodul...

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Autores: Jung, Hyunchul, Kim, Hong Sook, Kim, Jeong Yeon, Sun, Jong-Mu, Ahn, Jin Seok, Ahn, Myung-Ju, Park, Keunchil, Esteller, Manel, Lee, Se-Hoon, Choi, Jung Kyoon
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/155229
Acceso en línea:https://hdl.handle.net/2445/155229
Access Level:acceso abierto
Palabra clave:ADN
Metilació
Genètica
Immunologia
Tumors
DNA
Methylation
Genetics
Immunology
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repository_id_str
spelling DNA methylation loss promotes immune evasion of tumours with high mutation and copy number loadJung, HyunchulKim, Hong SookKim, Jeong YeonSun, Jong-MuAhn, Jin SeokAhn, Myung-JuPark, KeunchilEsteller, ManelLee, Se-HoonChoi, Jung KyoonADNMetilacióGenèticaImmunologiaTumorsDNAMethylationGeneticsImmunologyTumorsMitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy.Nature Publishing Group2020202020192020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion12 p.application/pdfhttps://hdl.handle.net/2445/155229Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1038/s41467-019-12159-9Nature Communications, 2019, vol. 10, num. 1, p. 4278https://doi.org/10.1038/s41467-019-12159-9cc-by (c) Jung, Hyunchul et al., 2019http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1552292026-05-29T05:05:01Z
dc.title.none.fl_str_mv DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
title DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
spellingShingle DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
Jung, Hyunchul
ADN
Metilació
Genètica
Immunologia
Tumors
DNA
Methylation
Genetics
Immunology
Tumors
title_short DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
title_full DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
title_fullStr DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
title_full_unstemmed DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
title_sort DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
dc.creator.none.fl_str_mv Jung, Hyunchul
Kim, Hong Sook
Kim, Jeong Yeon
Sun, Jong-Mu
Ahn, Jin Seok
Ahn, Myung-Ju
Park, Keunchil
Esteller, Manel
Lee, Se-Hoon
Choi, Jung Kyoon
author Jung, Hyunchul
author_facet Jung, Hyunchul
Kim, Hong Sook
Kim, Jeong Yeon
Sun, Jong-Mu
Ahn, Jin Seok
Ahn, Myung-Ju
Park, Keunchil
Esteller, Manel
Lee, Se-Hoon
Choi, Jung Kyoon
author_role author
author2 Kim, Hong Sook
Kim, Jeong Yeon
Sun, Jong-Mu
Ahn, Jin Seok
Ahn, Myung-Ju
Park, Keunchil
Esteller, Manel
Lee, Se-Hoon
Choi, Jung Kyoon
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ADN
Metilació
Genètica
Immunologia
Tumors
DNA
Methylation
Genetics
Immunology
Tumors
topic ADN
Metilació
Genètica
Immunologia
Tumors
DNA
Methylation
Genetics
Immunology
Tumors
description Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/155229
url https://hdl.handle.net/2445/155229
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41467-019-12159-9
Nature Communications, 2019, vol. 10, num. 1, p. 4278
https://doi.org/10.1038/s41467-019-12159-9
dc.rights.none.fl_str_mv cc-by (c) Jung, Hyunchul et al., 2019
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Jung, Hyunchul et al., 2019
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 12 p.
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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