{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:43:39Z","timestamp":1792716219708,"version":"4.5.0"},"reference-count":26,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T00:00:00Z","timestamp":1662508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: The methylation status of Septin 9 (SEPT9) and short stature homeobox 2 (SHOX2) 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 SEPT9 and SHOX2 methylation in prostate cancer (PCa) patient tissue and ccfDNA during prostate biopsy as a diagnostic tool. Methods: The methylation patterns of SEPT9 and SHOX2 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: SEPT9 and SHOX2 were hypermethylated in PCa tissue (p &lt; 0.001) and allowed discrimination of PCa and non-tumor prostate tissue (mSEPT9: AUC 0.87, 95%CI [0.82\u20130.92]; mSHOX2: AUC 0.89, 95%CI 0.84\u20130.94). SHOX2 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. SEPT9 and SHOX2 ccfDNA methylation allowed distinguishing patients with localized and metastatic disease (p &lt; 0.001 for both). In addition, methylation levels increased shortly after prostate biopsy only in patients with PCa (\u0394mSEPT9: p &lt; 0.001 and \u0394mSHOX2: p = 0.001). Conclusions: The early dynamics of methylated SEPT9 and SHOX2 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.<\/jats:p>","DOI":"10.3390\/cancers14184355","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T20:52:03Z","timestamp":1662583923000},"page":"4355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Early Dynamics of Quantitative SEPT9 and SHOX2 Methylation in Circulating Cell-Free Plasma DNA during Prostate Biopsy for Prostate Cancer Diagnosis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8213-9975","authenticated-orcid":false,"given":"Philipp","family":"Krausewitz","sequence":"first","affiliation":[{"name":"Department of Urology and Pediatric Urology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3258-0586","authenticated-orcid":false,"given":"Niklas","family":"Kluemper","sequence":"additional","affiliation":[{"name":"Department of Urology and Pediatric Urology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayk-Peter","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Urology and Pediatric Urology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"B\u00fcttner","sequence":"additional","affiliation":[{"name":"Department of Urology and Pediatric Urology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glen","family":"Kristiansen","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Ritter","sequence":"additional","affiliation":[{"name":"Department of Urology and Pediatric Urology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7526-0857","authenticated-orcid":false,"given":"J\u00f6rg","family":"Ellinger","sequence":"additional","affiliation":[{"name":"Department of Urology and Pediatric Urology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"561","DOI":"10.2217\/14796694.4.4.561","article-title":"Prostate Cancer: Psychosocial Implications and Management","volume":"4","author":"Roth","year":"2008","journal-title":"Future Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.crad.2007.05.022","article-title":"The Diagnostic Accuracy of CT and MRI in the Staging of Pelvic Lymph Nodes in Patients with Prostate Cancer: A Meta-Analysis","volume":"63","author":"Heesakkers","year":"2008","journal-title":"Clin. Radiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1056\/NEJMoa1910038","article-title":"Mri-Targeted, Systematic, And Combined Biopsy for Prostate Cancer Diagnosis","volume":"382","author":"Ahdoot","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1007\/s00345-022-04083-3","article-title":"Prospective Analysis of Pain Expectancy and Experience during Mr-Fusion Prostate Biopsy: Does Reality Match Patients\u2019 Expectancy?","volume":"40","author":"Krausewitz","year":"2022","journal-title":"World J. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1373\/clinchem.2019.310912","article-title":"Tumor-Associated Release of Prostatic Cells into the Blood after Transrectal Ultrasound-Guided Biopsy in Patients with Histologically Confirmed Prostate Cancer","volume":"66","author":"Joosse","year":"2020","journal-title":"Clin. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"39736","DOI":"10.1038\/srep39736","article-title":"Improved Detection of Circulating Tumor Cells in Non-Metastatic High-Risk Prostate Cancer Patients","volume":"6","author":"Kuske","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1001\/jama.2017.7248","article-title":"The Diagnosis and Treatment of Prostate Cancer: A Review","volume":"317","author":"Litwin","year":"2017","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"103166","DOI":"10.1016\/j.critrevonc.2020.103166","article-title":"The Main Sources of Circulating Cell-Free DNA: Apoptosis, Necrosis and Active Secretion","volume":"157","author":"Hu","year":"2021","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Galardi, F., De Luca, F., Romagnoli, D., Biagioni, C., Moretti, E., Biganzoli, L., Di Leo, A., Migliaccio, I., Malorni, L., and Benelli, M. (2020). Cell-Free DNA-Methylation-Based Methods and Applications in Oncology. Biomolecules, 10.","DOI":"10.3390\/biom10121677"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Palanca-Ballester, C., Rodriguez-Casanova, A., Torres, S., Calabuig-Fari\u00f1as, S., Exposito, F., Serrano, D., Redin, E., Valencia, K., Jantus-Lewintre, E., and Diaz-Lagares, A. (2021). Cancer Epigenetic Biomarkers in Liquid Biopsy for High Incidence Malignancies. Cancers, 13.","DOI":"10.3390\/cancers13123016"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.jmoldx.2020.04.205","article-title":"Treatment Response Monitoring in Patients with Advanced Malignancies Using Cell-Free Shox2 and Sept9 Dna Methylation in Blood: An Observational Prospective Study","volume":"22","author":"Jung","year":"2020","journal-title":"J. Mol. Diagn. Jmd"},{"key":"ref_12","first-page":"77","article-title":"Validation Of The Shox2\/Ptger4 Dna Methylation Marker Panel for Plasma-Based Discrimination Between Patients with Malignant and Nonmalignant Lung Disease","volume":"12","author":"Weiss","year":"2017","journal-title":"J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1136\/gutjnl-2012-304149","article-title":"Prospective Evaluation of Methylated Sept9 in Plasma for Detection of Asymptomatic Colorectal Cancer","volume":"63","author":"Church","year":"2014","journal-title":"Gut"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.juro.2015.10.172","article-title":"Development of Castration Resistant Prostate Cancer Can Be Predicted by a Dna Hypermethylation Profile","volume":"195","author":"Angulo","year":"2016","journal-title":"J. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1373\/clinchem.2016.270207","article-title":"Free-Circulating Methylated DNA in Blood for Diagnosis, Staging, Prognosis, and Monitoring of Head and Neck Squamous Cell Carcinoma Patients: An Observational Prospective Cohort Study","volume":"63","author":"Angulo","year":"2017","journal-title":"Clin. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/978-1-4939-7481-8_32","article-title":"DNA Methylation Analysis of Free-Circulating DNA in Body Fluids","volume":"1708","author":"Jung","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_17","first-page":"825","article-title":"Performance Evaluation of the DNA Methylation Biomarker Shox2 for the Aid in Diagnosis of Lung Cancer Based on the Analysis of Bronchial Aspirates","volume":"40","author":"Dietrich","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13148-017-0425-4","article-title":"Comparison of Quantification Algorithms for Circulating Cell-Free DNA Methylation Biomarkers in Blood Plasma from Cancer Patients","volume":"9","author":"Gevensleben","year":"2017","journal-title":"Clin. Epigenetics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.eururo.2019.02.033","article-title":"Prostate Imaging Reporting and Data System Version 2.1: 2019 Update of Prostate Imaging Reporting and Data System Version 2","volume":"76","author":"Turkbey","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.eururo.2020.09.042","article-title":"Eau-Eanm-Estro-Esur-Siog Guidelines on Prostate Cancer-2020 Update. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent","volume":"79","author":"Mottet","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_21","unstructured":"Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences, Lawrence Erlbaum Associates. [2nd ed.]."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/21681805.2020.1866659","article-title":"Natural History of Widespread High Grade Prostatic Intraepithelial Neoplasia and Atypical Small Acinar Proliferation: Should We Rebiopsy Them All?","volume":"55","author":"Oderda","year":"2021","journal-title":"Scand. J. Urol."},{"key":"ref_23","first-page":"24","article-title":"An Overview of Biomarkers in the Diagnosis and Management of Prostate Cancer","volume":"27","author":"Uhr","year":"2020","journal-title":"Can. J. Urol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"688274","DOI":"10.3389\/fmolb.2021.688274","article-title":"Analysis of the Prognostic Value and Gene Expression Mechanism of Shox2 in Lung Adenocarcinoma","volume":"8","author":"Li","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1002\/cncr.11821","article-title":"Clinical Features of Patients Who Present with Metastatic Prostate Carcinoma and Serum Prostate-Specific Antigen (Psa) Levels < 10 Ng\/Ml: The \u201cPsa Negative\u201d Patients","volume":"98","author":"Birtle","year":"2003","journal-title":"Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1097\/JU.0000000000000293","article-title":"Multicenter Optimization and Validation of a 2-Gene Mrna Urine Test for Detection of Clinically Significant Prostate Cancer before Initial Prostate Biopsy","volume":"202","author":"Haese","year":"2019","journal-title":"J. Urol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/18\/4355\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:24:41Z","timestamp":1760142281000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/18\/4355"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,7]]},"references-count":26,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["cancers14184355"],"URL":"https:\/\/doi.org\/10.3390\/cancers14184355","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,7]]}}}