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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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    1. Fangjie Zhu & Lucas Farnung & Eevi Kaasinen & Biswajyoti Sahu & Yimeng Yin & Bei Wei & Svetlana O. Dodonova & Kazuhiro R. Nitta & Ekaterina Morgunova & Minna Taipale & Patrick Cramer & Jussi Taipale, 2018. "The interaction landscape between transcription factors and the nucleosome," Nature, Nature, vol. 562(7725), pages 76-81, October.
    2. Timothy J. Richmond & Curt A. Davey, 2003. "The structure of DNA in the nucleosome core," Nature, Nature, vol. 423(6936), pages 145-150, May.
    3. Joshua Moss & Judith Magenheim & Daniel Neiman & Hai Zemmour & Netanel Loyfer & Amit Korach & Yaacov Samet & Myriam Maoz & Henrik Druid & Peter Arner & Keng-Yeh Fu & Endre Kiss & Kirsty L. Spalding & , 2018. "Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    4. Dimitrios Mathios & Jakob Sidenius Johansen & Stephen Cristiano & Jamie E. Medina & Jillian Phallen & Klaus R. Larsen & Daniel C. Bruhm & Noushin Niknafs & Leonardo Ferreira & Vilmos Adleff & Jia Yuee, 2021. "Detection and characterization of lung cancer using cell-free DNA fragmentomes," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    5. Yunyun An & Xin Zhao & Ziteng Zhang & Zhaohua Xia & Mengqi Yang & Li Ma & Yu Zhao & Gang Xu & Shunda Du & Xiang’an Wu & Shuowen Zhang & Xin Hong & Xin Jin & Kun Sun, 2023. "DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    6. Stephen Cristiano & Alessandro Leal & Jillian Phallen & Jacob Fiksel & Vilmos Adleff & Daniel C. Bruhm & Sarah Østrup Jensen & Jamie E. Medina & Carolyn Hruban & James R. White & Doreen N. Palsgrove &, 2019. "Genome-wide cell-free DNA fragmentation in patients with cancer," Nature, Nature, vol. 570(7761), pages 385-389, June.
    7. Netanel Loyfer & Judith Magenheim & Ayelet Peretz & Gordon Cann & Joerg Bredno & Agnes Klochendler & Ilana Fox-Fisher & Sapir Shabi-Porat & Merav Hecht & Tsuria Pelet & Joshua Moss & Zeina Drawshy & H, 2023. "A DNA methylation atlas of normal human cell types," Nature, Nature, vol. 613(7943), pages 355-364, January.
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