Histone modifications define distinct nucleosome positions in cell-free DNA

Histone-modification-associated nucleosome positions in prostate cancer cfDNA identify tumor fraction using a 50-MAP model, achieving AUCs of 0.91–0.96 across prostate, breast, and lung cancers.

• Why it matters: cfDNA fragmentation reflects nucleosome positioning, but whether nucleosome position variation can reveal chromatin states and histone modifications linked to tumor fraction and cancer state was unclear.
• What they did: Using cfChIP-seq on plasma from prostate cancer patients, the study identified 35,120 modification-associated positions (MAPs) for H3K4me2 and H3K9me3, then tested MAP protection across 2,535 cfDNA datasets and targeted panels.
• The result: MAP protection at a subset of MAPs correlated with tumor fraction (TF), and MAP-derived estimates correlated with reference TFs (r = 0.89) and longitudinal TF changes (r = 0.91), including neuroendocrine transformation detection via ASCL1 sites.