Cell-free DNA level tracks cancer methylation signal in 1,480-person study across 43 hospitals

A study in Proceedings of the National Academy of Sciences analyzed 1,480 previously untreated participants at 43 hospitals. The cohort included patients with 14 cancer types at all stages, patients with benign growths and healthy volunteers pnas.orgProceedings of the National Academy of Sciencespnas.orgOpen source ↗.

Cancer patients carry more circulating cell-free DNA (ccfDNA), small DNA fragments shed into the blood, than healthy people. Most of the excess comes from immune cells rather than from the tumor, which suggested it would dilute the much smaller amount of tumor-derived DNA in a sample.

Methylation rises with ccfDNA

The authors found the opposite: as total ccfDNA rose, it became enriched in fragments carrying cancer-associated methylation signatures. This held independent of cancer type, disease stage and a broad panel of demographic, clinical and technical covariates. Total ccfDNA explained more variance in the methylation signal than disease stage did. The authors suggest a coupling between immune cell activity and tumor methylation.

Detection sensitivity by concentration

Cancer detection sensitivity grew with ccfDNA concentration, including within individual stages. Stage I sensitivity ranged from 0.55 in the lowest concentration tertile to 0.85 in the highest; for stage II, from 0.59 to 0.86 pnas.orgProceedings of the National Academy of Sciencespnas.orgOpen source ↗. The authors propose considering ccfDNA concentration as a stage-independent stratification variable when benchmarking cancer-detection tests.

Similar behavior was seen in patients with symptomatic benign lesions. The authors interpret this as a broader response to abnormal tissue growth rather than something unique to malignancy.