Plasma cell-free DNA methylation-based prognosis in metastatic castrate-resistant prostate cancer

Molecular prognostication in metastatic castration-resistant prostate cancer (mCRPC) remains a challenge due to the lack of validated biomarkers. This study developed a plasma cell-free DNA (cfDNA) methylation-based prognostic model in mCRPC. Targeted cfDNA methylation sequencing in 96 prostate cancer patients across different states of cancer progression revealed 77 methylation haplotype blocks (MHBs) differentially methylated from organ-confined prostate cancer to mCRPC states. Among these 77 MHBs, the top 20 MHBs were associated with mCRPC overall survival and most MHB methylation levels positively correlated with predicted circulating tumor DNA (ctDNA) fraction. By integrating the MHB-based risk score with currently available prognostic clinical variables and ctDNA fraction, a prognostic nomogram was developed which showed high predictive performance for mCRPC survival (AUC = 0.99 for 6 months, AUC = 0.84 for 1 year, and AUC = 0.82 for 2 years). These findings demonstrate potential of cfDNA methylation as a molecular biology-driven biomarker for mCRPC prognosis.