{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T01:55:34Z","timestamp":1794102934760,"version":"4.8.0"},"reference-count":32,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T00:00:00Z","timestamp":1721347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chosun University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Bladder cancer prognosis remains a pressing clinical challenge, necessitating the identification of novel biomarkers for precise survival prediction and improved quality of life outcomes. This study proposes a comprehensive strategy to uncover key prognostic biomarkers in bladder cancer using DNA methylation analysis and extreme survival pattern observations in matched pairs of cancer and adjacent normal cells. Unlike traditional approaches that overlook cancer heterogeneity by analyzing entire samples, our methodology leverages patient-matched samples to account for this variability. Specifically, DNA methylation profiles from adjacent normal bladder tissue and bladder cancer tissue collected from the same individuals were analyzed to pinpoint critical methylation changes specific to cancer cells while mitigating confounding effects from individual genetic differences. Utilizing differential threshold settings for methylation levels within cancer-associated pathways enabled the identification of biomarkers that significantly impact patient survival. Our analysis identified distinct survival patterns associated with specific CpG sites, underscoring these sites\u2019 pivotal roles in bladder cancer outcomes. By hypothesizing and testing the influence of methylation levels on survival, we pinpointed CpG biomarkers that profoundly affect the prognosis. Notably, CpG markers, such as cg16269144 (PRKCZ), cg16624272 (PTK2), cg11304234, and cg26534425 (IL18), exhibited critical methylation thresholds that correlate with patient mortality. This study emphasizes the importance of tailored approaches to enhancing prognostic accuracy and refining therapeutic strategies for bladder cancer patients. The identified biomarkers pave the way for personalized prognostication and targeted interventions, promising advancements in bladder cancer management and patient care.<\/jats:p>","DOI":"10.3390\/medicina60071175","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T15:15:19Z","timestamp":1721402119000},"page":"1175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Unveiling Bladder Cancer Prognostic Insights by Integrating Patient-Matched Sample and CpG Methylation Analysis"],"prefix":"10.3390","volume":"60","author":[{"given":"Chanbyeol","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, Chosun University, Gwangju 61452, Republic of Korea"},{"name":"AI Convergence College, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangwon","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Chosun University, Gwangju 61452, Republic of Korea"},{"name":"AI Convergence College, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamin","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Chosun University, Gwangju 61452, Republic of Korea"},{"name":"AI Convergence College, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungsoo","family":"Gim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Chosun University, Gwangju 61452, Republic of Korea"},{"name":"AI Convergence College, Chosun University, Gwangju 61452, Republic of Korea"},{"name":"BK FOUR Department of Integrative Biological Science, Chosun University, Gwangju 61452, Republic of Korea"},{"name":"Well-Ageing Medicare Institute, Chosun University, Gwangju 61452, Republic of Korea"},{"name":"Asian Dementia Research Initiative, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA A Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1097\/CEJ.0000000000000594","article-title":"Progress in cancer mortality, incidence, and survival: A global overview","volume":"29","author":"Santucci","year":"2020","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.eururo.2021.08.010","article-title":"European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma In Situ)","volume":"81","author":"Babjuk","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.eururo.2020.03.055","article-title":"European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines","volume":"79","author":"Witjes","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/j.1464-410X.2009.09076.x","article-title":"The effect of age and gender on bladder cancer: A critical review of the literature","volume":"105","author":"Shariat","year":"2010","journal-title":"BJU Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.urolonc.2009.07.020","article-title":"Bladder cancer in the elderly","volume":"Volume 27","author":"Shariat","year":"2009","journal-title":"Urologic Oncology: Seminars and Original Investigations"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.urology.2004.03.034","article-title":"Aggressive treatment for bladder cancer is associated with improved overall survival among patients 80 years old or older","volume":"64","author":"Hollenbeck","year":"2004","journal-title":"Urology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6208","DOI":"10.1158\/0008-5472.CAN-07-6616","article-title":"RUNX3 methylation reveals that bladder tumors are older in patients with a history of smoking","volume":"68","author":"Wolff","year":"2008","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1200\/JCO.2005.03.163","article-title":"Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma","volume":"23","author":"Catto","year":"2005","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_10","first-page":"464","article-title":"Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients","volume":"8","author":"Chan","year":"2002","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/S0022-5347(17)38700-1","article-title":"Differential hypomethylation of the c-myc protooncogene in bladder cancers at different stages and grades","volume":"142","author":"Maestri","year":"1989","journal-title":"J. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nrc1045","article-title":"The power and the promise of DNA methylation markers","volume":"3","author":"Laird","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/5947","article-title":"Cancer-epigenetics comes of age","volume":"21","author":"Jones","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_14","first-page":"95","article-title":"Inhibition of DNA methylation by 5-aza-2\u2032-deoxycytidine suppresses the growth of human tumor cell lines","volume":"58","author":"Bender","year":"1998","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network (2014). Comprehensive molecular characterization of urothelial bladder carcinoma. Nature, 507, 315.","DOI":"10.1038\/nature12965"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/s12967-023-04056-z","article-title":"Comprehensive analysis of scRNA-Seq and bulk RNA-Seq reveals dynamic changes in the tumor immune microenvironment of bladder cancer and establishes a prognostic model","volume":"21","author":"Tan","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/bju.14047","article-title":"Impact of bladder cancer on health-related quality of life","volume":"121","author":"Smith","year":"2018","journal-title":"BJU Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1001\/jamaoncol.2017.4298","article-title":"Validation Study of the American Joint Committee on Cancer Eighth Edition Prognostic Stage Compared With the Anatomic Stage in Breast Cancer","volume":"4","author":"Weiss","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"180","DOI":"10.23736\/S2724-6051.22.04953-9","article-title":"Accuracy of the European Association of Urology (EAU) NMIBC 2021 scoring model in predicting progression in a large cohort of HG T1 NMIBC patients treated with BCG","volume":"75","author":"Contieri","year":"2023","journal-title":"Minerva Urol. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.3892\/ijo.2017.3893","article-title":"Gene expression profiling in bladder cancer identifies potential therapeutic targets","volume":"50","author":"Hussain","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0140-6736(09)60491-8","article-title":"Bladder cancer","volume":"374","author":"Kaufman","year":"2009","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.eururo.2016.08.037","article-title":"DNA repair in prostate cancer: Biology and clinical implications","volume":"71","author":"Mateo","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ccr.2012.02.014","article-title":"Metabolic reprogramming: A cancer hallmark even warburg did not anticipate","volume":"21","author":"Ward","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"28495","DOI":"10.1074\/jbc.270.48.28495","article-title":"Protein kinase C: Structure, function, and regulation","volume":"270","author":"Newton","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/nrc1647","article-title":"The role of focal-adhesion kinase in cancer\u2014A new therapeutic opportunity","volume":"5","author":"McLean","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0167-4889(01)00123-9","article-title":"Biochemical signals and biological responses elicited by the focal adhesion kinase","volume":"1540","author":"Schaller","year":"2001","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/nrc3792","article-title":"FAK in cancer: Mechanistic findings and clinical applications","volume":"14","author":"Sulzmaier","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.semnephrol.2006.09.013","article-title":"Interleukin-18 and the pathogenesis of inflammatory diseases","volume":"Volume 27","author":"Dinarello","year":"2007","journal-title":"Seminars in Nephrology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nrg1655","article-title":"DNA methylation and human disease","volume":"6","author":"Robertson","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1056\/NEJMra072067","article-title":"Epigenetics in cancer","volume":"358","author":"Esteller","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1158\/1078-0432.CCR-06-2076","article-title":"DNA methylation as a therapeutic target in cancer","volume":"13","author":"Issa","year":"2007","journal-title":"Clin. Cancer Res."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/7\/1175\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:20:00Z","timestamp":1760109600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/7\/1175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,19]]},"references-count":32,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["medicina60071175"],"URL":"https:\/\/doi.org\/10.3390\/medicina60071175","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,19]]}}}