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Cell-free DNA (cfDNA) fragmentomics offers a promising non-invasive approach to improve screening accuracy and risk stratification. In this study, we enrolled 106 prostate cancer patients and 114 high-risk non-cancer individuals to develop a cfDNA fragmentomics-based screening assay using plasma whole-genome sequencing. Two fragmentomic features\u2014copy number variation and fragment size profile\u2014were incorporated into machine learning models for training and evaluated in an independent validation cohort of 83 cancer patients and 76 non-cancer individuals. The fragmentomics-based model achieved an area under the curve (AUC) of 0.933 in the training cohort (66.0% sensitivity at 95.6% specificity; 51.9% sensitivity at 98.2% specificity) with good calibration (slope: 0.957; intercept: 0.001), and maintained strong performance in the validation cohort (AUC: 0.887; 57.8% sensitivity at 92.1% specificity), showing rising predictive probabilities and sensitivity across advancing stages (Stage I\u2013IV: 27.3% to 77.8%). Importantly, the model performed well in the PSA grey zone (4\u201310\u00a0ng\/mL) with an AUC of 0.865 (69.0% sensitivity at 81.8% specificity). When integrated with total PSA levels, the combined algorithm achieved an AUC of 0.915 in the validation cohort and improved sensitivity at 98% specificity (Stage I\u2013IV: 30.0% to 87.5%). These findings support the clinical potential of our cfDNA fragmentomic assay, particularly when combined with PSA, as a highly accurate and non-invasive tool for early prostate cancer detection.<\/jats:p>","DOI":"10.1186\/s12964-025-02522-3","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T14:56:16Z","timestamp":1764428176000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["DECIPHER-PRAD: an advanced fragmentomics-based cell-free DNA assay for prostate cancer early detection"],"prefix":"10.1186","volume":"24","author":[{"given":"Shun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanchen","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fufeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junlong","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqian","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"issue":"1","key":"2522_CR1","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.eururo.2019.08.005","volume":"77","author":"MB Culp","year":"2020","unstructured":"Culp MB, Soerjomataram I, Efstathiou JA, Bray F, Jemal A. 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All participants provided written informed consent to participate.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All participants provided written informed consent to publish data collected in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Authors H.B., M.W., X.Z., T.D., F.W., S.C., and Y.S. are employees of Nanjing Geneseeq Technology Inc. All other authors declare no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2"}}