DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
Jung, Hyunchul (KAIST Department of Bio and Brain Engineering (Daejeon, (República de Corea))
Kim, Hong Sook (Sungkyunkwan University (Seül, República de Corea))
Kim, Jeong Yeon (KAIST Department of Bio and Brain Engineering (Daejeon, (República de Corea))
Sun, Jong-Mu (Sungkyunkwan University (Seül, República de Corea))
Ahn, Jin Seop (Sungkyunkwan University (Seül, República de Corea))
Ahn, Myung-Ju (Sungkyunkwan University (Seül, República de Corea))
Park, Keunchil (Sungkyunkwan University (Seül, República de Corea))
Esteller, M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Lee, Se-Hoon (Sungkyunkwan University (Seül, República de Corea))
Choi, Jung Kyoon (KAIST Department of Bio and Brain Engineering (Daejeon, (República de Corea))
Universitat Autònoma de Barcelona

Fecha:	2019
Resumen:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Aneuploidy ; Biomarkers, Tumor ; Cell Proliferation ; CpG Islands ; DNA Copy Number Variations ; DNA Methylation ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic ; Humans ; Mutation Rate ; Neoplasms ; Promoter Regions, Genetic ; Tumor Escape
Publicado en:	Nature communications, Vol. 10 Núm. 1 (january 2019) , p. 4278, ISSN 2041-1723

DOI: 10.1038/s41467-019-12159-9
PMID: 31537801

12 p, 3.6 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
Artículos > Artículos de investigación
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