Pre-diagnosis plasma cell-free DNA reveals early signatures of prostate and breast cancer risk up to eight years prior to clinical detection.

Genome-wide cell-free DNA (cfDNA) methylation profiling of 491 pre-diagnosis breast and prostate cancer plasma samples, some collected up to nine years before diagnosis, identifies early cancer-associated epigenetic alterations and predictive signatures. Differentially methylated regions were enriched in regulatory and repetitive elements and reflected cancer-tissue- and immune-cell-associated DNA methylation patterns. Logistic regression models trained on discovery set samples showed that cfDNA silencer-region methylation robustly predicted future prostate cancer, with high-risk individuals exhibiting a 3.55-fold increased hazard of developing prostate cancer. Enhancer hypermethylation modestly predicted incident breast cancer but strongly distinguished established late-stage breast cancers, with high-risk individuals showing a 2.3-fold increased hazard. These results highlight cfDNA methylation as a promising biomarker for early cancer risk prediction and surveillance.