A mathematical model of cell-free DNA fragment size reveals cancer-specific fragmentomic patterns

A mathematical model of cell-free DNA fragment size reveals cancer-specific fragmentomic patterns | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A mathematical model of cell-free DNA fragment size reveals cancer-specific fragmentomic patterns Ze Zhou, Wendy Cooper, Sara Lightowlers, Charlotte Coles, Amit Roshan, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7677707/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Analysis of cell-free DNA (cfDNA) fragmentomic features shows promise for minimally invasive cancer diagnostics. The size distribution of cfDNA molecules has emerged as a novel analytical dimension enhancing ctDNA detection. Here, we propose a mathematical model of cfDNA length distribution across multiple biodiy flulids, deconvoluted into a series of peaks (components) represented by the Cauchy–Lorentz distribution with an approximate 10 bp periodicity. This model provides a new analytical framework for investigating the biological mechanisms of cfDNA fragmentation and release, leading to the identification of a previously uncharacterized 159 bp fragment length, that may indicate a demarcation between intra- and inter-nucleosome-derived cfDNA. Furthermore, we demonstrate that tumor-specific ctDNA shortening and phagocytosis-associated cfDNA shortening can be differentiated through analysis of the amplitudes and scales of intra- and inter-nucleosomal components. Moreover, leveraging ctDNA-specific alterations revealed by cfDNA size profile deconvolution analysis could significantly enhance cancer detection. Health sciences/Biomarkers/Diagnostic markers Biological sciences/Cancer/Tumour biomarkers Full Text Additional Declarations There is NO Competing Interest. Sauer et al. EMBO Mol Med. 2022 Aug 8;14(8):e15729. All mouse work conducted was approved by and performed in accordance with the ethical regulations and guidelines of the Home Office UK and the CRUK CI Animal Welfare and Ethics Review Board (PPL number: PP7478310). Supplementary Files SupplementaryData.xlsx Dataset 1-9 FigS1.pptx Figure S1 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7677707","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":519520195,"identity":"5fb22092-f090-4734-a975-aa27b4e32c34","order_by":0,"name":"Ze Zhou","email":"","orcid":"","institution":"Cancer Research UK Cambridge Institute","correspondingAuthor":false,"prefix":"","firstName":"Ze","middleName":"","lastName":"Zhou","suffix":""},{"id":519520196,"identity":"71e82d63-23fa-41b3-bcf8-16939e94f8fe","order_by":1,"name":"Wendy Cooper","email":"","orcid":"https://orcid.org/0000-0003-3416-9982","institution":"University of 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