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

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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 hyper-methylation. 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 hypo-methylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy.
Publisher
NATURE PUBLISHING GROUP
Issue Date
ACCEPT
Language
English
Article Type
Article
Citation

NATURE COMMUNICATIONS, v.10

ISSN
2041-1723
DOI
10.1038/s41467-019-12159-9
URI
http://hdl.handle.net/10203/267847
Appears in Collection
BiS-Journal Papers(저널논문)
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