| Summary: | Background: The methylation status of <i>Septin 9</i> (<i>SEPT9</i>) and <i>short stature homeobox 2</i> (<i>SHOX2</i>) in circulating cell-free DNA (ccfDNA) are validated pan-cancer biomarkers. The present proof-of-concept study aimed to investigate the potential and dynamics of quantitative <i>SEPT9</i> and <i>SHOX2</i> methylation in prostate cancer (PCa) patient tissue and ccfDNA during prostate biopsy as a diagnostic tool. Methods: The methylation patterns of <i>SEPT9</i> and <i>SHOX2</i> in prostate tissue were analyzed using The Cancer Genome Atlas data set (n = 498 PCa and n = 50 normal adjacent prostate tissue (NAT)). Next, dynamic changes of ccfDNA methylation were quantified in prospectively enrolled patients undergoing prostate biopsy (n = 72), local treatment for PCa (n = 7; radical prostatectomy and radiotherapy) as well as systemic treatment for PCa (n = 6; chemotherapy and 177-Lu-PSMA-therapy). Biomarker levels were correlated with clinicopathological parameters. Results: <i>SEPT9</i> and <i>SHOX2</i> were hypermethylated in PCa tissue (<i>p</i> < 0.001) and allowed discrimination of PCa and non-tumor prostate tissue (<i>mSEPT9</i>: AUC 0.87, 95%CI [0.82–0.92]; <i>mSHOX2</i>: AUC 0.89, 95%CI 0.84–0.94). <i>SHOX2</i> methylation and mRNA levels were significantly higher in PCa tissue and increased with tumor stage and grade, as well as in patients suffering from biochemical recurrence following radical prostatectomy. <i>SEPT9</i> and <i>SHOX2</i> ccfDNA methylation allowed distinguishing patients with localized and metastatic disease (<i>p</i> < 0.001 for both). In addition, methylation levels increased shortly after prostate biopsy only in patients with PCa (Δ<i>mSEPT9</i>: <i>p</i> < 0.001 and Δ<i>mSHOX2</i>: <i>p</i> = 0.001). Conclusions: The early dynamics of methylated <i>SEPT9</i> and <i>SHOX2</i> in ccfDNA allow differentiation between PCa patients and patients without PCa and is a promising marker for tumor monitoring in the metastatic stage to determine tumor burden under systemic therapy.
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