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

Hyunchul Jung, Hong Sook Kim, Jeong Yeon Kim, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Manel Esteller, Se-Hoon Lee () and Jung Kyoon Choi ()
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Hyunchul Jung: Department of Bio and Brain Engineering, KAIST
Hong Sook Kim: Sungkyunkwan University School of Medicine
Jeong Yeon Kim: Department of Bio and Brain Engineering, KAIST
Jong-Mu Sun: Sungkyunkwan University School of Medicine
Jin Seok Ahn: Sungkyunkwan University School of Medicine
Myung-Ju Ahn: Sungkyunkwan University School of Medicine
Keunchil Park: Sungkyunkwan University School of Medicine
Manel Esteller: Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet
Se-Hoon Lee: Sungkyunkwan University School of Medicine
Jung Kyoon Choi: Department of Bio and Brain Engineering, KAIST

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12159-9

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