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Cell-free DNA size deconvolution resolves nucleosomal origins and reveals tumor-associated fragmentomic alterations

Year: 2026
Type: article
Abstract: Analysis of cell-free DNA (cfDNA) fragmentomic features holds great promise for minimally invasive cancer diagnostics. Although selectively analyzing short plasma cfDNA enriches tumor-derived DNA (ctDNA), the mechanisms shaping cfDNA size profiles remain incompletely understood. Here, we develop a generalized model of cfDNA fragment length distributions across multiple bodily fluids (saliva, urine, cerebrospinal fluid, lymphatic fluid, and plasma), deconvoluting size profiles into ~10-bp periodic peaks (components), each approximated by a Cauchy-Lorentz distribution. This analytical framework enables investigation of cfDNA fragmentation across diverse pathological states and reveals a 159-bp component that may demarcate intra- and inter-nucleosomal cfDNA. By analyzing plasma DNA from individuals harboring germline TP53 mutations, patients receiving radiotherapy, and liver transplantation recipients, we demonstrate that ctDNA shortening can be distinguished from phagocytosis-associated cfDNA shortening through differences in the amplitude and scale parameters of intra- and inter-nucleosomal components. Moreover, leveraging tumor-related fragmentomic alterations, characterized by increased fragmentation entropy identified through cfDNA size deconvolution, significantly enhances cancer detection.
DOI: 10.1038/s41467-026-72925-4
Authors: Ze Zhou, Wendy N. Cooper, Zhao Cheng, Sara Lightowlers, Charlotte E. Coles, Amit Roshan, Nitzan Rosenfeld, Hui Zhao
Institutions: Queen Mary University of London, University of Cambridge, Cancer Research UK, Cancer Research UK Cambridge Center, Barts Cancer Institute, Cambridge University Hospitals NHS Foundation Trust
Language: English
Subfield: Cancer Research
Open Access status: gold
Estimated APC paid: $6,990
Funders: Mark Foundation For Cancer Research, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Royal College of Surgeons of England, Servier, National Institutes of Health, NIHR Cambridge Biomedical Research Centre
Awards: G139696651, G1673962618, G1834682469, G2088128697, G2193660476, G2198857803, G2367376091, G242731019, G2493601830, G2537968379, G2633902757, G270946572, G2830747971, G296294689, G299057155, G3004532622, G3119561655, G3584577881, G3594106981, G370598735, G4197410787, G4268089617, G438229647, G4655236649, G4995451912, G510844398, G515689015, G5167650663, G5364368985, G5495922725, G5741036609, G6052482428, G6077662935, G63586632, G6541669631, G6887062956, G6900120486, G7069699392, G7229355336, G7423961978, G7669185616, G7782972677, G7791803505, G8683158713, G8848839487, G8942440830, G8959774080
OpenAlex ID: W7160626757
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