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DNA methylation and gene expression as determinants of genome-wide cell-free DNA fragmentation

Author

Listed:
  • Michaël Noë

    (Johns Hopkins University School of Medicine
    Netherlands Cancer Institute)

  • Dimitrios Mathios

    (Johns Hopkins University School of Medicine)

  • Akshaya V. Annapragada

    (Johns Hopkins University School of Medicine)

  • Shashikant Koul

    (Johns Hopkins University School of Medicine)

  • Zacharia H. Foda

    (Johns Hopkins University School of Medicine)

  • Jamie E. Medina

    (Johns Hopkins University School of Medicine)

  • Stephen Cristiano

    (Johns Hopkins University School of Medicine)

  • Christopher Cherry

    (Johns Hopkins University School of Medicine)

  • Daniel C. Bruhm

    (Johns Hopkins University School of Medicine)

  • Noushin Niknafs

    (Johns Hopkins University School of Medicine)

  • Vilmos Adleff

    (Johns Hopkins University School of Medicine)

  • Leonardo Ferreira

    (Johns Hopkins University School of Medicine)

  • Hari Easwaran

    (Johns Hopkins University School of Medicine)

  • Stephen Baylin

    (Johns Hopkins University School of Medicine)

  • Jillian Phallen

    (Johns Hopkins University School of Medicine)

  • Robert B. Scharpf

    (Johns Hopkins University School of Medicine)

  • Victor E. Velculescu

    (Johns Hopkins University School of Medicine)

Abstract

Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection.

Suggested Citation

  • Michaël Noë & Dimitrios Mathios & Akshaya V. Annapragada & Shashikant Koul & Zacharia H. Foda & Jamie E. Medina & Stephen Cristiano & Christopher Cherry & Daniel C. Bruhm & Noushin Niknafs & Vilmos Ad, 2024. "DNA methylation and gene expression as determinants of genome-wide cell-free DNA fragmentation," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50850-8
    DOI: 10.1038/s41467-024-50850-8
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    References listed on IDEAS

    as
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