Analysis of a cell-free DNA-based cancer screening cohort links fragmentomic profiles, nuclease levels, and plasma DNA concentrations

Yasine Malki ^1,2,3, Guannan Kang ^1,2,3, W K Jacky Lam ^1,2,3,4

⁰Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China.

Genome Research +

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November 27, 2024

View abstract on PubMed

Summary

Inter-individual differences in circulating cell-free DNA (cfDNA) concentrations are linked to DNA clearance mechanisms. Fragmentomic patterns reveal variations in cfDNA levels, impacting liquid biopsy accuracy.

Area Of Science

Biochemistry
Genomics
Molecular Biology

Background

Plasma cell-free DNA (cfDNA) concentration is crucial for liquid biopsy reliability.
Biological factors driving inter-individual cfDNA concentration variability are largely unknown.
cfDNA concentration is determined by a balance between DNA release and clearance.

Purpose Of The Study

To investigate the role of nuclease-mediated cfDNA clearance in inter-individual cfDNA concentration differences.
To analyze cfDNA fragmentomic profiles and their correlation with cfDNA concentration.
To explore machine learning applications for inferring cfDNA concentration and fractions.

Main Methods

Fragmentomic analysis of plasma cfDNA from 862 healthy individuals.
End motif deconvolution analysis to identify contributing nucleases.
Machine learning models to predict cfDNA concentration from fragmentomic data.

Main Results

Increasing cfDNA concentrations correlated with larger DNA fragments, reduced short fragments, and increased G-end motifs.
Decreased contribution of DNASE1L3 and DFFB nucleases observed in individuals with higher cfDNA.
Machine learning accurately inferred cfDNA concentration from fragmentomic profiles.

Conclusions

Nuclease-mediated clearance is a key determinant of plasma cfDNA concentration.
Distinct cfDNA fragmentomic patterns are associated with varying cfDNA levels.
This understanding enhances the measurement of clinically relevant cfDNA, such as fetal and tumor DNA.