Speaker
Description
Liquid biopsy studies consistently report both elevated circulating cell-free DNA (cfDNA) concentrations and shortened fragment lengths in cancer. These features are often attributed to tumor-specific processes, despite tumor-derived cfDNA frequently constituting less than 1% of the total. Here, we consider an alternative explanation: Saturation of cfDNA clearance, which prolongs cfDNA circulation time, increases exposure to plasma nucleases, causing fragments to shorten. By combining a mechanistic model of cfDNA fragmentation with analyses of two independent cancer patient cohorts, and publicly available clearance-perturbation experiments, we show that elevated cfDNA levels in cancer patients are accompanied by a characteristic leftward shift in fragment length distributions consistent with impaired hepatic clearance. This signature is highly correlated with cfDNA concentration, independent of circulating tumor DNA (ctDNA) fraction, and independently prognostic of patient survival. In contrast to hepatic clearance reduction, DNA-protecting antibodies cause a systematic rise in short cfDNA fragments. Our model allows us to directly identify the parameter governing fragmentation kinetics and predict the effect of antibody priming on cfDNA concentration. Together, these results identify saturating clearance as a central determinant of cfDNA abundance and fragment length. More broadly, they highlight the value of mechanistic modeling of clearance processes in extracting clinically meaningful signals from cfDNA fragmentation data.
