CtDNA

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that is not associated with cells. ctDNA should not be confused with cell-free DNA (cfDNA), a broader term which describes DNA that is freely circulating in the bloodstream, but is not necessarily of tumor origin. Because ctDNA may reflect the entire tumor genome, it has gained traction for its potential clinical utility; “liquid biopsies” in the form of blood draws may be taken at various time points to monitor tumor progression throughout the treatment regimen.

ctDNA originates directly from the tumor or from circulating tumor cells (CTCs),^[1] which describes viable, intact tumor cells that shed from primary tumors and enter the bloodstream or lymphatic system. The precise mechanism of ctDNA release is unclear. The biological processes postulated to be involved in ctDNA release include apoptosis and necrosis from dying cells, or active release from viable tumor cells.^{[2][3][4][5][6]} Studies in both human (healthy and cancer patients)^[7] and xenografted mice^[8] show that the size of fragmented cfDNA is predominantly 166bp long, which corresponds to the length of DNA wrapped around a nucleosome plus a linker. Fragmentation of this length is indicative of apoptotic DNA fragmentation, suggesting that apoptosis may be the primary method of ctDNA release.

In healthy tissue, infiltrating phagocytes are responsible for clearance of apoptotic or necrotic cellular debris, which includes cfDNA.^[9] Levels of cfDNA in healthy patients is only present at low levels but higher levels of ctDNA in cancer patients can be detected. This possibly occurs due to inefficient immune cell infiltration to tumor sites, which reduces effective clearance of ctDNA from the bloodstream.^[9]