biostudies-literatureUnknown7(2)Zeng YCell-free DNA analysis via methylation and fragmentation profiling has advanced minimally invasive cancer detection; however, broader application has been limited by small cohorts and inconsistent data processing. Here we collated 1,074 cfMeDIP-seq profiles across 9 studies, comprising cancer samples from 11 cancer types, carriers of Li-Fraumeni syndrome and healthy controls. We developed a uniform computational workflow to mitigate technical and biological confounders across cohorts. This analysis identified 14,202 pancancer differentially methylated regions for cancer detection, along with cancer-specific markers for subtype monitoring. Fragmentomic profiling revealed distinguishing differences in 5' end motifs, fragment lengths and nucleosome footprints across cancers. Integrating methyNature cancer384-398https://www.ebi.ac.uk/biostudies/studies/S-EPMC12948677biostudies-literatureA pan-cancer compendium of 1,294 plasma cell-free DNA methylomes and fragmentomes enabling multicancer detection.PMC12948677Lok BHHe HHYe WWong DLupien MStutheit-Zhao EYCheng NDe Carvalho DDBratman SVHoffman MMZadeh GChen KPugh TJSanz-Garcia EBell EAwadalla PZeng YWilson SLZnassi NNotta FFang YGhanekar AKim RHLuo PAbelman DDMain SCMohanraj SSinghawansa AfalseA pan-cancer compendium of 1,294 plasma cell-free DNA methylomes and fragmentomes enabling multicancer detection.Cell-free DNA analysis via methylation and fragmentation profiling has advanced minimally invasive cancer detection; however, broader application has been limited by small cohorts and inconsistent data processing. Here we collated 1,074 cfMeDIP-seq profiles across 9 studies, comprising cancer samples from 11 cancer types, carriers of Li-Fraumeni syndrome and healthy controls. We developed a uniform computational workflow to mitigate technical and biological confounders across cohorts. This analysis identified 14,202 pancancer differentially methylated regions for cancer detection, along with cancer-specific markers for subtype monitoring. Fragmentomic profiling revealed distinguishing differences in 5' end motifs, fragment lengths and nucleosome footprints across cancers. Integrating methy2026-01-01T00:00:00Z2026 Feb2026-07-16T23:10:03.973Z2026-07-12T03:11:15.401ZS-EPMC129486774171482410.1038/s43018-026-01116-3