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Moreover, current prognostic tools including Gleason scoring and tumor staging demonstrate limited accuracy for predicting disease progression and tumor recurrence. DNA methylation serves as a stable epigenetic modification that directly regulates gene expression, making it an ideal biomarker for cancer prognosis. Therefore, this study leveraged whole-genome enzymatic methylation sequencing on 120 patients to develop a novel prognostic signature for aggressive prostate cancer progression. We analyzed 20,849 differentially methylated regions (DMRs) and employed multiple machine learning approaches to identify optimal biomarkers. This revealed a 14-region DNA methylation signature that can serve as independent prognostic prediction factors outperforming traditional clinical indices. Further, when combined into a risk score it achieved a clinically meaningful odds ratio. This methylation-based approach provides actionable information for treatment decisions and surveillance strategies, representing a significant advancement toward precision medicine in prostate cancer management through biologically informed risk stratification.<\/jats:p>","DOI":"10.1242\/bio.062281","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T11:14:56Z","timestamp":1765278896000},"source":"Crossref","is-referenced-by-count":0,"title":["Methylation-based signature to distinguish indolent and aggressive prostate cancer"],"prefix":"10.1242","volume":"14","author":[{"given":"Muheng","family":"Liao","sequence":"first","affiliation":[{"name":"Washington University School of Medicine 1 Department of Internal Medicine , , St Louis, MO 63110 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jace","family":"Webster","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine 1 Department of Internal Medicine , , St Louis, MO 63110 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Ly","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine 1 Department of Internal Medicine , , St Louis, MO 63110 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Rozycki","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine 1 Department of Internal Medicine , , St Louis, MO 63110 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1728-4614","authenticated-orcid":false,"given":"Christopher A.","family":"Maher","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine 1 Department of Internal Medicine , , St Louis, MO 63110 ,","place":["USA"]},{"name":"Washington University School of Medicine 2 Alvin J. 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