{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:28:46Z","timestamp":1764052126182,"version":"3.45.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Oncol. Rev."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Early prognostication in non-muscle-invasive bladder cancer (NMIBC) is essential for optimizing therapy and follow-up. Epigenetic mechanisms, particularly DNA methylation, have emerged as promising biomarkers for predicting disease outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>A systematic review and meta-analysis were conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate the prognostic significance of promoter DNA methylation in NMIBC. Comprehensive searches of PubMed, Web of Science, Embase, MEDLINE, and the Cochrane Library (January 2010\u2013October 2022) identified eligible studies. The Newcastle\u2013Ottawa scale was used for quality assessment, and pooled hazard ratios with 95% confidence intervals were calculated using random-effects models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eleven studies with 3,065 NMIBC patients were analyzed. Promoter methylation was significantly associated with poor progression-free survival (pooled hazard ratios (HR) = 2.88; 95% CI = 2.03\u20134.09; p &amp;lt; 0.0001) and recurrence-free survival (pooled HR = 2.65; 95% CI = 1.93\u20133.63; p &amp;lt; 0.0001). Although overall survival showed pathway-specific variation (pooled HR = 0.96; 95% CI = 0.36\u20132.60; p = 0.94), methylation of adhesion and apoptosis-related genes exhibited the strongest associations. Subgroup analyses revealed a greater prognostic impact in Asian cohorts (p &amp;lt; 0.0001), suggesting regional differences in epigenetic susceptibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Promoter DNA methylation constitutes a robust prognostic biomarker for recurrence and progression in NMIBC, with stronger effects in Asian populations. Standardization of validated gene panels, assay thresholds, and cross-regional prospective validation will be essential for clinical translation. Integrating methylation-based classifiers into risk stratification models could improve individualized management and long-term outcomes in NMIBC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/or.2025.1679974","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:25:11Z","timestamp":1764051911000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["DNA methylation as prognostic factors in non-muscle-invasive bladder cancer: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"19","author":[{"given":"Vishwajeet","family":"Singh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mukul Kumar","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashutosh","family":"Shrivastava","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dinesh Kumar","family":"Sahu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayank","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuj Kumar","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"123","DOI":"10.14740\/wjon1210","article-title":"Non-muscle invasive bladder cancer: a review of the current trend in Africa","volume":"10","author":"Cassell","year":"2019","journal-title":"World J Oncol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1007\/s13337-021-00742-y","article-title":"Associated pathogenesis of bladder cancer and SARS-CoV-2 infection: a treatment strategy","volume":"32","author":"Singh","year":"2021","journal-title":"Virusdisease"},{"key":"B4","doi-asserted-by":"publisher","first-page":"486.e25","DOI":"10.1016\/j.urolonc.2023.09.008","article-title":"The relationship between BCG immunotherapy and oxidative stress parameters in patients with nonmuscle invasive bladder cancer","volume":"41","author":"Singh","year":"2023","journal-title":"Urol Oncol Semin Original Invest"},{"key":"B5","doi-asserted-by":"publisher","first-page":"322","DOI":"10.4103\/njms.njms_62_22","article-title":"Immunotherapeutic and their immunological aspects: current treatment strategies and agents","volume":"13","author":"Jain","year":"2022","journal-title":"Natl J Maxill Surg"},{"key":"B6","doi-asserted-by":"publisher","first-page":"12596","DOI":"10.3390\/ijms241612596","article-title":"BCG-unresponsive non-muscle-invasive bladder cancer: current treatment landscape and novel emerging molecular targets","volume":"24","author":"Claps","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s12291-024-01187-y","article-title":"Metabolomic biomarkers for prognosis in non-muscle invasive bladder cancer: a comprehensive systematic review and meta-analysis","volume":"2024","author":"Singh","year":"2024","journal-title":"Indian J Clin Biochem"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e35623","DOI":"10.7759\/cureus.35623","article-title":"Management of metastatic renal cell carcinoma in a tertiary care hospital","volume":"15","author":"Kumar","year":"2023","journal-title":"Cureus"},{"key":"B9","doi-asserted-by":"publisher","first-page":"452.e1","DOI":"10.1016\/j.urolonc.2024.07.017","article-title":"The role of autophagy dysregulation in low and high-grade nonmuscle invasive bladder cancer: a survival analysis and clinicopathological association","volume":"42","author":"Kumar","year":"2024","journal-title":"Urol Oncol Semin Original Invest"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e65816","DOI":"10.7759\/cureus.65816","article-title":"Evaluation of fibroblast growth factor receptor 3 (FGFR3) and tumor protein P53 (TP53) as independent prognostic biomarkers in high-grade non-muscle invasive bladder cancer","volume":"16","author":"Kumar","year":"2024","journal-title":"Cureus"},{"key":"B11","doi-asserted-by":"publisher","first-page":"104262","DOI":"10.1016\/j.esmoop.2025.104262","article-title":"101P survival analysis and clinicopathological correlation with molecular classification in BCG-Nonresponsive Ta-T1 bladder cancer","volume":"10","author":"Singh","year":"2025","journal-title":"ESMO Open"},{"key":"B12","doi-asserted-by":"publisher","first-page":"S1515","DOI":"10.1016\/j.annonc.2024.10.305","article-title":"285P genetic variation of the inflammatory cytokine interleukin 17 in non-muscle invasive bladder cancer","volume":"35","author":"Singh","year":"2024","journal-title":"Ann Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"148","DOI":"10.3390\/genes8060148","article-title":"CpG and Non-CpG methylation in epigenetic gene regulation and brain function","volume":"8","author":"Jang","year":"2017","journal-title":"Genes (Basel)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1186\/2193-1801-3-178","article-title":"Promoter hypermethylation of tumor suppressor genes correlates with tumor grade and invasiveness in patients with urothelial bladder cancer","volume":"3","author":"Bilgrami","year":"2014","journal-title":"SpringerPlus"},{"key":"B15","doi-asserted-by":"publisher","first-page":"355.e9","DOI":"10.1016\/j.urolonc.2023.04.022","article-title":"CYP1A1 gene polymorphism and heavy metal analyses in benign prostatic hyperplasia and prostate cancer: an explorative case-control study","volume":"41","author":"Singh","year":"2023","journal-title":"Urol Oncol Semin Original Invest"},{"key":"B16","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3390\/cells2030545","article-title":"DNA methylation and apoptosis resistance in cancer cells","volume":"2","author":"Hervouet","year":"2013","journal-title":"Cells"},{"key":"B17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/B978-0-323-99879-6.00003-1","article-title":"Chapter 3 - tumor cell metabolism and autophagy as therapeutic targets","volume-title":"Autophagy and metabolism","author":"Poojary","year":"2022"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.3390\/cancers17081283","article-title":"Novel urinary biomarkers for the detection of bladder cancer","volume":"17","author":"Oyaert","year":"2025","journal-title":"Cancers"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e1230","DOI":"10.1002\/cl2.1230","article-title":"PRISMA2020: an R package and shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and open synthesis","volume":"18","author":"Haddaway","year":"2022","journal-title":"Campbell Syst Rev"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1016\/j.juro.2010.05.085","article-title":"Myopodin methylation is associated with clinical outcome in patients with T1G3 bladder cancer","volume":"184","author":"Alvarez-Mugica","year":"2010","journal-title":"J Urol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"E501","DOI":"10.1002\/ijc.27319","article-title":"Novel combination markers for predicting progression of nonmuscle invasive bladder cancer","volume":"131","author":"Ha","year":"2012","journal-title":"Int J Cancer"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1016\/j.ejso.2012.07.116","article-title":"RUNX3 methylation in normal surrounding urothelium of patients with non-muscle-invasive bladder cancer: potential role in the prediction of tumor progression","volume":"38","author":"Jeong","year":"2012","journal-title":"Eur J Surg Oncol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1002\/ijc.28121","article-title":"HOXA9, ISL1 and ALDH1A3 methylation patterns as prognostic markers for nonmuscle invasive bladder cancer: array-based DNA methylation and expression profiling","volume":"133","author":"Kim","year":"2013","journal-title":"Int J Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.clgc.2011.12.003","article-title":"Ras association domain family 1A: a promising prognostic marker in recurrent nonmuscle invasive bladder cancer","volume":"10","author":"Kim","year":"2012","journal-title":"Clin genitourinary Cancer"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2015\/402963","article-title":"Clinical implications and prognostic values of prostate cancer susceptibility candidate methylation in primary nonmuscle invasive bladder cancer","volume":"2015","author":"Kim","year":"2015","journal-title":"Dis Markers"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e1131","DOI":"10.3892\/or.2015.4409","article-title":"RSPH9 methylation pattern as a prognostic indicator in patients with non-muscle invasive bladder cancer","volume":"195","author":"Kim","year":"2016","journal-title":"J Urol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.12659\/msm.892130","article-title":"Aberrant methylation of CDH13 is a potential biomarker for predicting the recurrence and progression of non-muscle-invasive bladder cancer","volume":"20","author":"Ma","year":"2014","journal-title":"Med Sci Monitor"},{"key":"B28","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/preaccept-1759254111327153","article-title":"Clinical significance of protocadherin 8 (PCDH8) promoter methylation in non-muscle invasive bladder cancer","volume":"33","author":"Lin","year":"2014","journal-title":"J Exp and Clin Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1158\/1078-0432.ccr-17-2719","article-title":"Molecular markers increase precision of the european association of urology non-muscle-invasive bladder cancer progression risk groups","volume":"24","author":"van Kessel","year":"2018","journal-title":"Clin Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.jmoldx.2014.04.007","article-title":"Molecular classification of Non\u2013muscle-invasive bladder cancer (PTa low-grade, pT1 low-grade, and pT1 high-grade subgroups) using methylation of tumor-suppressor genes","volume":"16","author":"Sacristan","year":"2014","journal-title":"J Mol Diagn"},{"key":"B31","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1007\/s10654-010-9491-z","article-title":"Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses","volume":"25","author":"Stang","year":"2010","journal-title":"Eur J Epidemiol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1038\/s41418-020-00647-1","article-title":"RUNX3 methylation drives hypoxia-induced cell proliferation and antiapoptosis in early tumorigenesis","volume":"28","author":"Lee","year":"2021","journal-title":"Cell Death and Differ"},{"key":"B33","doi-asserted-by":"publisher","first-page":"6127","DOI":"10.3390\/ijms26136127","article-title":"T-Cadherin (CDH13) and non-coding RNAs: the crosstalk between health and disease","volume":"26","author":"Rubina","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.1093\/carcin\/bgr120","article-title":"Epigenetic regulation of cellular adhesion in cancer","volume":"32","author":"Katto","year":"2011","journal-title":"Carcinogenesis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e920665","DOI":"10.12659\/msm.920665","article-title":"Protocadherin 8 (PCDH8) inhibits proliferation, migration, invasion, and angiogenesis in esophageal squamous cell carcinoma","volume":"26","author":"Yu","year":"2020","journal-title":"Med Sci Monitor"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1002\/cac2.12602","article-title":"FGFR3 alterations in bladder cancer: sensitivity and resistance to targeted therapies","volume":"44","author":"Noeraparast","year":"2024","journal-title":"Cancer Commun (London, England)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1126\/science.aao0535","article-title":"Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism","volume":"357","author":"Chiba","year":"2017","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.mrrev.2016.11.002","article-title":"TERT promoter mutations in telomere biology","volume":"771","author":"Heidenreich","year":"2017","journal-title":"Mutat Res Rev Mutat Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1158\/2326-6066.cir-15-0110","article-title":"Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC","volume":"4","author":"Gabrielson","year":"2016","journal-title":"Cancer Immunol Res"},{"key":"B40","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.juro.2015.02.2941","article-title":"CD103+ tumor infiltrating lymphocytes predict a favorable prognosis in urothelial cell carcinoma of the bladder","volume":"194","author":"Wang","year":"2015","journal-title":"J Urol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e000452","DOI":"10.1136\/jitc-2019-000452","article-title":"CD103+ tumor-resident CD8+ T cell numbers underlie improved patient survival in oropharyngeal squamous cell carcinoma","volume":"8","author":"Hewavisenti","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B42","doi-asserted-by":"publisher","first-page":"4104","DOI":"10.1245\/s10434-015-4431-5","article-title":"Genetic variations in glutathione pathway genes predict cancer recurrence in patients treated with transurethral resection and bacillus calmette-guerin instillation for non-muscle invasive bladder cancer","volume":"22","author":"Ke","year":"2015","journal-title":"Ann Surg Oncol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.euo.2018.06.011","article-title":"Performance of the bladder EpiCheck methylation test for patients under surveillance for non-muscle-invasive bladder cancer: results of a multicenter, prospective, blinded clinical trial","volume":"1","author":"Witjes","year":"2018","journal-title":"Eur Urol Oncol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"237","DOI":"10.3390\/jpm11030237","article-title":"Liquid biopsy biomarkers in urine: a route towards molecular diagnosis and personalized medicine of bladder cancer","volume":"11","author":"Ferro","year":"2021","journal-title":"J personalized Med"},{"key":"B45","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1007\/s00345-024-05287-5","article-title":"Bladder cancer detection by urinary methylation markers GHSR\/MAL: a validation study","volume":"42","author":"Beijert","year":"2024","journal-title":"World J Urol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"2649","DOI":"10.1158\/0008-5472.can-18-2331","article-title":"MITF expression predicts therapeutic vulnerability to p300 inhibition in human melanoma","volume":"79","author":"Kim","year":"2019","journal-title":"Cancer Res"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1016\/j.chembiol.2017.06.012","article-title":"Tumor organoids as a pre-clinical cancer model for drug discovery","volume":"24","author":"Weeber","year":"2017","journal-title":"Cell Chem Biol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e16580","DOI":"10.1200\/jco.2025.43.16_suppl.e16580","article-title":"Elucidating the epigenetic landscape of non-muscle invasive bladder cancer","volume":"43","author":"Falick Michaeli","year":"2025","journal-title":"J Clin Oncol"}],"container-title":["Oncology Reviews"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/or.2025.1679974\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:25:12Z","timestamp":1764051912000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/or.2025.1679974\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":48,"alternative-id":["10.3389\/or.2025.1679974"],"URL":"https:\/\/doi.org\/10.3389\/or.2025.1679974","relation":{},"ISSN":["1970-5557"],"issn-type":[{"value":"1970-5557","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]},"article-number":"1679974"}}