Age-stratified reference intervals unlock the clinical potential of circulating cell-free DNA as a biomarker of poor outcome for healthy individuals and patients with colorectal cancer

Circulating cell‐free DNA (cfDNA) has spurred much interest as a biomarker in oncology. However, inter‐ and intra‐individual cfDNA levels vary greatly. Consequently, in order to base clinical decisions on cfDNA measurements, normal reference intervals are essential to avoid that ordinary variation is confused with clinically relevant change. The lack of reference intervals may potentially explain the ambiguous results reported in the field. Our study aimed to establish reference intervals and to evaluate the association between cfDNA and demographic and clinical variables, including colorectal cancer (CRC). Plasma samples and clinical data from 2817 subjects were collected including 1930 noncancer individuals and 887 CRC patients. cfDNA was measured using droplet digital polymerase chain reaction (PCR). The large cohort combined with robust cfDNA quantification enabled establishment of reference intervals (
What's new? Circulating cell‐free DNA (cfDNA) has spurred much interest as a potential biomarker in oncology. However, large inter‐ and intra‐individual variations have led to ambiguous study results and hampered the identification of clinically relevant changes. This study analyzes circulating cfDNA levels in a large cohort of 2817 individuals, with 887 colorectal cancer patients among them. The use of age‐stratified cfDNA reference intervals reveals that aberrant cfDNA levels are prognostic of overall survival in both cancer and non‐cancer individuals, independently of age, gender, and multimorbidity. Altogether, the results could facilitate the interpretation of cfDNA cancer research and clinical use of cfDNA biomarkers.