Journal
JCI INSIGHT
Volume 6, Issue 7, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.144561
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Funding
- INSERM
- SIRIC Montpellier Cancer Grant [INCa_Inserm_DGOS_12553]
- European Union [755333]
- H2020 Societal Challenges Programme [755333] Funding Source: H2020 Societal Challenges Programme
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The study reveals that circulating cell-free DNA exhibits a specific fragmentation pattern, primarily inserted in nucleosomes or chromatin and affected by continuous nuclease activity. The size distribution of cfDNA can be used for quality control and samples with a higher proportion of malignant cell-derived cfDNA show increased fragmentation and nuclease activity.
distribution of circulating cell-free DNA (cfDNA) using whole-genome sequencing (WGS) from both double- and single-strand DNA library preparations (DSP and SSP, n = 7) and using quantitative PCR (Q-PCR, n = 116). The size profile in healthy individuals was remarkably homogenous when using DSP sequencing or SSP sequencing. CfDNA size profile had a characteristic nucleosome fragmentation pattern. Overall, our data indicate that the proportion of cfDNA inserted in mononucleosomes, di-nucleosomes, and chromatin of higher molecular size (>1000 bp) can be estimated as 67.5% to 80%, 9.4% to 11.5%, and 8.5% to 21.0%, respectively. Although DNA on single chromatosomes or mono-nucleosomes is detectable, our data revealed that cfDNA is highly nicked (97%-98%) on those structures, which appear to be subjected to continuous nuclease activity in the bloodstream. Fragments analysis allows the distinction of cfDNA of different origins: first, cfDNA size profile analysis may be useful in cfDNA extract quality control; second, subtle but reliable differences between metastatic colorectal cancer patients and healthy individuals vary with the proportion of malignant cell-derived cfDNA in plasma extracts, pointing to a higher degree of cfDNA fragmentation and nuclease activity in samples with high malignant cell cfDNA content.
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