The comings and goings of cell-free DNA: Biological and clinical implications

Cell-free DNA (cfDNA) has emerged as a pivotal biomarker with significant implications across medical fields, including non-invasive prenatal testing and oncology. As cfDNA reflects the physiological and pathological states of the body, a detailed understanding of the biology of cfDNA, including the origins, production, circulation, and clearance, is crucial for advancing its diagnostic applications. This review offers a detailed account of the current understanding of the biology of cfDNA, integrating findings to explore mechanistic insights underlying the production and clearance of cfDNA. We discuss how this interplay is altered in various pathophysiological states-including cancer, pregnancy, systemic lupus erythematosus, infectious diseases, and transplantation-and highlight areas that warrant further characterization. Understanding these processes is essential in studying cfDNA dynamics in health and disease, providing novel insights that could expedite developments that further expand the utility of cfDNA-based diagnostic tests, and pave the way for more personalized applications of cfDNA.