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

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 Adleff, Leonardo Ferreira, Hari Easwaran, Stephen Baylin, Jillian Phallen, Robert B. Scharpf () and Victor E. Velculescu ()
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Michaël Noë: Johns Hopkins University School of Medicine
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

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50850-8

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