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

Author

Listed:
  • 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
    Centro de Investigacion Biomedica en Red Cancer (CIBERONC)
    Institucio Catalana de Recerca i Estudis Avançats (ICREA)
    University of Barcelona (UB))

  • Se-Hoon Lee

    (Sungkyunkwan University School of Medicine
    Sungkyunkwan University)

  • Jung Kyoon Choi

    (Department of Bio and Brain Engineering, KAIST
    Penta Medix Co., Ltd.)

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.

Suggested Citation

  • Hyunchul Jung & Hong Sook Kim & Jeong Yeon Kim & Jong-Mu Sun & Jin Seok Ahn & Myung-Ju Ahn & Keunchil Park & Manel Esteller & Se-Hoon Lee & Jung Kyoon Choi, 2019. "DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12159-9
    DOI: 10.1038/s41467-019-12159-9
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    1. Dzana Dervovic & Ahmad A. Malik & Edward L. Y. Chen & Masahiro Narimatsu & Nina Adler & Somaieh Afiuni-Zadeh & Dagmar Krenbek & Sebastien Martinez & Ricky Tsai & Jonathan Boucher & Jacob M. Berman & K, 2023. "In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Jae-Won Cho & Seyeon Park & Gamin Kim & Heonjong Han & Hyo Sup Shim & Sunhye Shin & Yong-Soo Bae & Seong Yong Park & Sang-Jun Ha & Insuk Lee & Hye Ryun Kim, 2021. "Dysregulation of TFH-B-TRM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Brian D. Lehmann & Antonio Colaprico & Tiago C. Silva & Jianjiao Chen & Hanbing An & Yuguang Ban & Hanchen Huang & Lily Wang & Jamaal L. James & Justin M. Balko & Paula I. Gonzalez-Ericsson & Melinda , 2021. "Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes," Nature Communications, Nature, vol. 12(1), pages 1-18, December.

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