Since their initial description in 19481, small DNA fragments travelling in the non-cellular component of internal bodily fluids and excretions have revolutionized numerous fields in public health and preventive medicine2,3,4,5,6. Although its origins have been a topic of controversy, cell-free DNA (cfDNA) is generally thought to arise from cellular breakdown mechanisms but also through active release from living cells7.

Generally, cfDNA circulates in fragments ranging between 120–220 bp, or multiples thereof, with a maximum peak at 167 bp. This pattern agrees with the length of DNA wrapped around a single nucleosome, plus a short stretch of ~ 20 bp (linker DNA) bound to a histone H13,8. As nucleosome positioning varies between different tissues, and in malignant neoplasms, the local pattern of fragmentation has been shown to aid in determining the predominant cell-type of origin contributing to the cfDNA pool9,10.

The analysis of altered nucleosome fingerprints, together with outstanding advances regarding the characterization of the cfDNA methylome, hold promise regarding the detection and classification of even early-stage cancers10,11.