biostudies-literatureZhou XNational Institute of Environmental Health SciencesNIEHS NIH HHSNHGRI NIH HHSCincinnati Children's Hospital Medical CenterNational Human Genome Research Institute138https://www.ebi.ac.uk/biostudies/studies/S-EPMC9733064biostudies-literatureUnknown14(1)The fine-scale cell-free DNA fragmentation patterns in early-stage cancers are poorly understood. We developed a de novo approach to characterize the cell-free DNA fragmentation hotspots from plasma whole-genome sequencing. Hotspots are enriched in open chromatin regions, and, interestingly, 3'end of transposons. Hotspots showed global hypo-fragmentation in early-stage liver cancers and are associated with genes involved in the initiation of hepatocellular carcinoma and associated with cancer stem cells. The hotspots varied across multiple early-stage cancers and demonstrated high performance for the diagnosis and identification of tissue-of-origin in early-stage cancers. We further validated the performance with a small number of independent case-control-matched early-stage cancer samplesGenome medicineCRAG: de novo characterization of cell-free DNA fragmentation hotspots in plasma whole-genome sequencing.PMC9733064start-up grant, Trustee Award, CCTST mentored pilot translational award, and CCHMC innovation grantR56 HG012360P30ES006096R56HG012360R24 ES028527P30 ES006096R24ES028527Liu YZheng HFu HDillehay McKillip KLPinney SMZhou XfalseCRAG: de novo characterization of cell-free DNA fragmentation hotspots in plasma whole-genome sequencing.The fine-scale cell-free DNA fragmentation patterns in early-stage cancers are poorly understood. We developed a de novo approach to characterize the cell-free DNA fragmentation hotspots from plasma whole-genome sequencing. Hotspots are enriched in open chromatin regions, and, interestingly, 3'end of transposons. Hotspots showed global hypo-fragmentation in early-stage liver cancers and are associated with genes involved in the initiation of hepatocellular carcinoma and associated with cancer stem cells. The hotspots varied across multiple early-stage cancers and demonstrated high performance for the diagnosis and identification of tissue-of-origin in early-stage cancers. We further validated the performance with a small number of independent case-control-matched early-stage cancer samples2022-01-01T00:00:00Z2022 Dec2025-04-19T06:40:01.749Z2025-04-19T06:40:01.749ZS-EPMC97330643648248710.1186/s13073-022-01141-8