Genome-wide methylome profiling of cell-free DNA enables prognostication of patients with castration-resistant prostate cancer

Abstract Background Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with few biomarkers to inform treatment selection or patient prognosis. Methylation profiles of plasma circulating tumour DNA (ctDNA) accurately reflect tumour methylomes and may reveal novel biomarkers of mCRPC. Methods To establish a novel mCRPC-associated methylation signature for detection of ctDNA, we performed plasma methylome profiling on 27 mCRPC patients and 10 controls (cohort 1). Signature-based ctDNA detection was evaluated across prostate cancer (PC) disease stages using an internal cohort of 93 PC patients and 8 controls (cohort 2), and an external cohort of 115 PC patients (cohort 3). Results We established a 48-region methylation signature (cfMeCaP) capable of highly sensitive detection of ctDNA in mCRPC (100%, 84% and 95% in cohorts 1, 2 and 3, respectively). cfMeCaP methylation at mCRPC diagnosis was associated with poor progression-free survival (PFS) and overall survival in all three cohorts ( p < 0.005), independent of routine clinical variables. Persistent serial detection of ctDNA using cfMeCaP was strongly associated with rapid mCRPC treatment failure (median PFS 4.4 vs. 65.5 months; p < 0.0001), while no detection predicted continued treatment response. Conclusion These results highlight cfMeCaP as a promising non-invasive biomarker for prognostication in mCRPC.