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.
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Cancer Research UK (C507/A27657, C9545/A29580, SEBINT-2024/100003, C1287/A26886, EDDRPG-May24/100002 & C36857/A27548), NIHR Cambridge Biomedical Research Center (BRC-1215-20014), The Mark Foundation for Cancer Research (RG95043), the Cancer Research UK Cambridge Center (C9685/A25177), and Addenbrooke's Charitable Trust (ACT 9800). This work was supported by the Cancer Molecular Diagnostics Lab, University of Cambridge, which is funded by Cancer Research UK Cambridge Center [CTRQQR-2021\100012] and the NIHR Cambridge Biomedical Research Center (NIHR203312). Neo-RT was funded by Breast Cancer Now, and this work also falls under the umbrella of CRUK RadNet Cambridge. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. N.R. is supported by infrastructure grants within the CRUK City of London Major Center Awards [C7893/A26233 and CTRQQR-2021\100004]. A.R. is supported by CRUK-Royal College of Surgeons of England Clinician Scientist Fellowship [C64667/A27958]. C.E.C was funded by the National Institute of Health and Care Research (NIHR) and supported by the NIHR Cambridge Biomedical Research Center. The authors acknowledge the use of images from Servier Medical Art (CC BY 4.0) and NIH BioArt (Public Domain) in the preparation of Fig. 1a.
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Z.Z., N.R., and H.Z. are inventors on a patent application entitled “Methods of cancer detection” (Application No. GB2520112.0), which relates to the detection of cancer in cell-free DNA and is not directly described in this manuscript. The patent is managed by Cancer Research Horizons in accordance with its policies. The remaining authors declare no competing interests.
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Zhou, Z., Cooper, W.N., Cheng, Z. et al. Cell-free DNA size deconvolution resolves nucleosomal origins and reveals tumor-associated fragmentomic alterations. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72925-4
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DOI: https://doi.org/10.1038/s41467-026-72925-4
