Fig. 2.

Origins of circulating tumour DNA in the blood. (A) Haematopoietic cells are the predominant source of basal cfDNA levels in both cancer patients and healthy individuals, with fragments bearing distinct epigenetic characteristics consistent with lymphoid and myeloid cells-of-origin. In contrast, tumour lesions comprise a complex mixture of neoplastic cells and cells of the surrounding microenvironment, including stromal cells, immune cells and endothelial cells. These different cell types shed varying levels of tumour-derived ctDNA into the pool of circulating cfDNA throughout tumorigenesis and disease progression. (B) ctDNA can be released into the circulation during tumour cell apoptosis, necrosis or active secretion via extracellular vesicles and/or proliferating tumour cells. (C) Mechanisms of ctDNA clearance from the blood are less well understood, but likely include digestion by nucleases, renal uptake or clearance by the liver and spleen. ctDNA, circulating tumour DNA; cfDNA, cell-free DNA; EV, extracellular vesicles; TME, tumour microenvironment.