Early-stage cancer results in a multiplicative increase in cell-free DNA originating from healthy tissue

Cell-free DNA is a promising biomarker for cancer detection. However, the sources of elevated cell-free DNA (cfDNA) in patients with early-stage cancer, and the mechanisms by which cfDNA is shed into, and subsequently cleared from the circulation are still poorly understood. Leveraging a rich dataset of cfDNA in healthy individuals and early-stage cancer patients, we find a multiplicative increase in cfDNA concentration in the presence of cancer. This increase is cancer type-specific, ranging from a ∼1.3-fold increase in lung cancer, to a ∼12-fold increase in liver cancer, and does not originate from tumor, but from healthy tissue. Employing an additional dataset reporting the tissue of origin of cfDNA, we observe a significant increase in the correlation between cfDNA originating from leukocytes and from non-leukocyte sources in cancer patients. Introducing a mathematical model for cfDNA dynamics, we find that the observed correlation can be explained by a saturation mechanism in cfDNA clearance. Saturation in clearance implies that smaller increases in cfDNA shedding may lead to proportionally larger increases in cfDNA levels. Our findings quantify cfDNA dynamics in patients with cancer, with implications for improving the accuracy of liquid biopsies for early cancer detection.