ArticleGenome research2025
Analysis of a cell-free DNA-based cancer screening cohort links fragmentomic profiles, nuclease levels, and plasma DNA concentrations.
Article in Genome research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Circulating Cell-free DNA as a biomarker for radiation-induced injury: From mechanistic insights to clinical translation.Cancer metastasis reviews · 2026Review
- Long-read sequencing identifies aberrant fragmentation patterns linked to elevated cell-free DNA levels in cancer.Genome biology · 2026Article
- Holistic determination of ends of cfDNA molecules.Cell genomics · 2026Article
- Liquid biopsy epigenetics: establishing a molecular profile based on cell-free DNA.Molecular oncology · 2026Review
- DNAvi: integration, statistics, and visualization of cell-free DNA fragment traces.Bioinformatics (Oxford, England) · 2026Article
- The circulating cell-free DNA landscape in sepsis is dominated by impaired liver clearance.Cell genomics · 2025Article
- Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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Authors and funding
23 authors.
Funding
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Abstract
The concentration of circulating cell-free DNA (cfDNA) in plasma is an important determinant of the robustness of liquid biopsies. However, biological mechanisms that lead to inter-individual differences in cfDNA concentrations remain unexplored. The concentration of plasma cfDNA is governed by an interplay between its release and clearance. We hypothesized that cfDNA clearance by nucleases might be one mechanism that contributes toward inter-individual variations in cfDNA concentrations. We performed fragmentomic analysis of the plasma cfDNA from 862 healthy individuals, with a cfDNA concentration range of 1.61-41.01 ng/mL. We observed an increase in large DNA fragments (231-600 bp), a decreased frequencies of shorter DNA fragments (20-160 bp), and an increased frequency of G-end motifs with increasing cfDNA concentrations. End motif deconvolution analysis revealed a decreased contribution of DNASE1L3 and DFFB in subjects with higher cfDNA concentration. The five subjects with the highest plasma DNA concentration (top 0.58%) had aberrantly decreased levels of DNASE1L3 protein in plasma. The cfDNA concentration could be inferred from the fragmentomic profile through machine learning and was well correlated to the measured cfDNA concentration. Such an approach could infer the fractional DNA concentration from particular tissue types, such as the fetal and tumor fraction. This work shows that individuals with different cfDNA concentrations are associated with characteristic fragmentomic patterns of the cfDNA pool and that nuclease-mediated clearance of DNA is a key parameter that affects cfDNA concentration. Understanding these mechanisms has facilitated the enhanced measurement of cfDNA species of clinical interest, including circulating fetal and tumor DNA.
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