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, both 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 that early-stage cancer results in a multiplicative increase in the concentration of cfDNA. Our results demonstrate that this increase in cfDNA does not originate from the tumor, but from healthy-tissue, implying that the presence of cancer either increases cell turnover of healthy cfDNA-shedding cells, or slows down clearance of cfDNA by a cancer-type specific factor. This finding is further corroborated by the fact that, for each cancer type, we observe similar multiplicative increases in the concentration of mutant DNA fragments in plasma that contain mutations originating from non-tumor sources. The magnitude of the multiplicative increase in cfDNA concentration varies greatly between cancer types, ranging from a ∼1.3-fold increase in lung cancer, to a ∼12-fold increase in patients with liver cancer. As cfDNA is cleared in the liver, the large increase in patients with liver cancer may imply that the systemic increase in cfDNA levels in the presence of cancer is due to slower clearance rate rather than higher cell turnover. Our findings quantify cfDNA dynamics in patients with cancer, with implications for improving the accuracy of liquid biopsies for early cancer detection. ### Competing Interest Statement The authors have declared no competing interest.