Circulating DNA reveals nucleosome occupancy patterns that are associated with nucleosome-DNA affinity and are affected in cancer

The study of cell-free circulating DNA (cirDNA) fragments (fragmentomics) from liquid biopsies has received increasing attention. By constructing an atlas of these well-positioned nucleosomes, which we called WPNA, we found that their occupancy was associated with histone-DNA affinity, as evidenced by codon usage bias and differences in cirDNA fragment sizes. Moreover, WPNA nucleosome occupancy was different in healthy and cancer samples, thus allowing developing a high-performance machine learning approach for cancer detection (specificity and sensitivity >0.95 for seven cancer types). Cancer influenced WPNA nucleosome occupancy in a global manner, although distinct cancer types retained specific features. WPNA nucleosome occupancy at transcription factor binding sites revealed shared, pan-cancer regulation of transcriptional programs involved in hematopoietic cell differentiation and neutrophil biology, the main cirDNA sources. This work provides new fundamental insights into cirDNA and DNA sequence using cirDNA as a physical readout. It also bares translational significance by disclosing a new high-performance strategy for cancer detection from liquid biopsies.