{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:40:52Z","timestamp":1760035252003,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Council","award":["NSTC 113-2314-B-039-054","NSTC 112-2314-B-039-032","CMU113-MF-64"],"award-info":[{"award-number":["NSTC 113-2314-B-039-054","NSTC 112-2314-B-039-032","CMU113-MF-64"]}]},{"DOI":"10.13039\/501100004391","name":"China Medical University","doi-asserted-by":"publisher","award":["NSTC 113-2314-B-039-054","NSTC 112-2314-B-039-032","CMU113-MF-64"],"award-info":[{"award-number":["NSTC 113-2314-B-039-054","NSTC 112-2314-B-039-032","CMU113-MF-64"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>GATA3 is a transcription factor involved in urothelial differentiation and is widely used as a diagnostic marker for urothelial carcinoma (UC). Although loss of GATA3 expression has been linked to more aggressive disease, its prognostic significance remains uncertain. Genetic variation within the GATA3 locus, particularly rs1244159, may influence protein expression and clinical outcomes. We conducted a case control study in Taiwan including 461 UC cases and 586 controls genotyped for four GATA3 SNPs. GATA3 expression was assessed via immunohistochemistry (IHC) in 98 tumor tissues. Logistic regression and Kaplan\u2013Meier analyses were used to evaluate SNP associations and survival outcomes. An XGBoost-based machine learning model with SHAP (SHapley Additive exPlanations) was applied to rank survival predictors. The rs1244159 G allele was associated with a significantly reduced UC risk (adjusted OR = 0.48, p = 0.0231) and higher GATA3 expression (p = 0.0173). High GATA3 expression predicted improved overall survival (p = 0.0092), particularly among G allele carriers (p = 0.0071). SHAP analysis identified age, chemotherapy, and GATA3 expression as the top predictors of survival, consistent with Cox regression results. In conclusion, our integrative analysis suggests that the rs1244159 G allele modulates GATA3 expression and influences UC prognosis. Combining genomics, pathology, and machine learning, GATA3 may serve as a clinically useful biomarker for risk stratification and outcome prediction in UC.<\/jats:p>","DOI":"10.3390\/ijms26136378","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T09:08:44Z","timestamp":1751447324000},"page":"6378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Analysis of GATA3 Expression and Variants as Prognostic Biomarkers in Urothelial Cancer"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1759-2279","authenticated-orcid":false,"given":"Chia-Min","family":"Chung","sequence":"first","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404328, Taiwan"},{"name":"Department of Psychiatry and Center for Addiction and Mental Health, China Medical University Hospital, Taichung 404327, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao-Hsiang","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Urology, College of Medicine, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Huei","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Urology, College of Medicine, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Po-Jen","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Urology, College of Medicine, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Shun","family":"Lien","sequence":"additional","affiliation":[{"name":"Department of Urology, College of Medicine, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9673-2430","authenticated-orcid":false,"given":"Chi-Jung","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Public Health, China Medical University, Taichung City 406040, Taiwan"},{"name":"Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Saginala, K., Barsouk, A., Aluru, J.S., Rawla, P., Padala, S.A., and Barsouk, A. (2020). Epidemiology of Bladder Cancer. Med. Sci., 8.","DOI":"10.3390\/medsci8010015"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.eururo.2013.11.046","article-title":"EAU guidelines on muscle-invasive and metastatic bladder cancer: Summary of the 2013 guidelines","volume":"65","author":"Witjes","year":"2014","journal-title":"Eur. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.eururo.2023.04.020","article-title":"Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights","volume":"84","author":"Koutros","year":"2023","journal-title":"Eur. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/ng.687","article-title":"A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci","volume":"42","author":"Rothman","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Figueroa, J.D., Koutros, S., Colt, J.S., Kogevinas, M., Garcia-Closas, M., Real, F.X., Friesen, M.C., Baris, D., Stewart, P., and Schwenn, M. (2015). Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms. J. Natl. Cancer Inst., 107.","DOI":"10.1093\/jnci\/djv223"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1002\/mc.21932","article-title":"Systematic evaluation of bladder cancer risk-associated single-nucleotide polymorphisms in a Chinese population","volume":"52","author":"Ma","year":"2013","journal-title":"Mol. Carcinog."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1158\/1055-9965.EPI-06-0743","article-title":"Risk of bladder cancer associated with family history of cancer: Do low-penetrance polymorphisms account for the increase in risk?","volume":"16","author":"Silverman","year":"2007","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.eururo.2012.07.033","article-title":"Epidemiology and risk factors of urothelial bladder cancer","volume":"63","author":"Burger","year":"2013","journal-title":"Eur. Urol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/nrc3817","article-title":"Molecular biology of bladder cancer: New insights into pathogenesis and clinical diversity","volume":"15","author":"Knowles","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.humpath.2022.09.004","article-title":"GATA3 expression loss is linked to stage progression but is unrelated to prognosis in muscle-invasive urothelial carcinoma of the bladder","volume":"130","author":"Plage","year":"2022","journal-title":"Hum. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0925-4773(99)00088-X","article-title":"Embryonic expression of the human GATA-3 gene","volume":"85","author":"Debacker","year":"1999","journal-title":"Mech. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1097\/PAS.0b013e318260cde7","article-title":"Utility of GATA3 immunohistochemistry in differentiating urothelial carcinoma from prostate adenocarcinoma and squamous cell carcinomas of the uterine cervix, anus, and lung","volume":"36","author":"Chang","year":"2012","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ebiom.2016.08.036","article-title":"Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use","volume":"12","author":"Dadhania","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/modpathol.2013.76","article-title":"GATA3 expression in paragangliomas: A pitfall potentially leading to misdiagnosis of urothelial carcinoma","volume":"26","author":"So","year":"2013","journal-title":"Mod. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1016\/j.humpath.2012.02.011","article-title":"GATA binding protein 3 is down-regulated in bladder cancer yet strong expression is an independent predictor of poor prognosis in invasive tumor","volume":"43","author":"Miyamoto","year":"2012","journal-title":"Hum. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wang, C.C., Tsai, Y.C., and Jeng, Y.M. (2019). Biological significance of GATA3, cytokeratin 20, cytokeratin 5\/6 and p53 expression in muscle-invasive bladder cancer. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0221785"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.humpath.2017.04.003","article-title":"GATA3 immunohistochemistry in urothelial carcinoma of the upper urinary tract as a urothelial marker and a prognosticator","volume":"64","author":"Inoue","year":"2017","journal-title":"Hum. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"151397","DOI":"10.1016\/j.anndiagpath.2019.08.001","article-title":"Prognostic stratification of muscle invasive urothelial carcinomas using limited immunohistochemical panel of Gata3 and cytokeratins 5\/6, 14 and 20","volume":"43","author":"Jangir","year":"2019","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1007\/s11684-019-0687-7","article-title":"Expression status of GATA3 and mismatch repair proteins in upper tract urothelial carcinoma","volume":"13","author":"Wang","year":"2019","journal-title":"Front. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1016\/j.humpath.2014.02.023","article-title":"Differential expression of GATA-3 in urothelial carcinoma variants","volume":"45","author":"Liang","year":"2014","journal-title":"Hum. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s00428-019-02618-5","article-title":"Immunohistochemical assessment of basal and luminal markers in non-muscle invasive urothelial carcinoma of bladder","volume":"475","author":"Chaux","year":"2019","journal-title":"Virchows Arch."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yuk, H.D., Jeong, C.W., Kwak, C., Kim, H.H., Moon, K.C., and Ku, J.H. (2019). Clinical outcomes of muscle invasive bladder Cancer according to the BASQ classification. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6042-1"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"945","DOI":"10.2147\/OTT.S237099","article-title":"Biological and Clinical Significance of GATA3 Detected from TCGA Database and FFPE Sample in Bladder Cancer Patients","volume":"13","author":"Wang","year":"2020","journal-title":"OncoTargets Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1002\/ijc.35250","article-title":"Smoking behavior and the risks of tumor recurrence and progression in patients with non-muscle-invasive bladder cancer","volume":"156","author":"Kiebach","year":"2025","journal-title":"Int. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wang, M., Jian, Z., Gao, X., Yuan, C., Jin, X., Li, H., and Wang, K. (2021). Causal Associations Between Educational Attainment and 14 Urological and Reproductive Health Outcomes: A Mendelian Randomization Study. Front. Public Health, 9.","DOI":"10.3389\/fpubh.2021.742952"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wu, Y.R., Li, C.C., Juan, Y.S., Li, W.M., Wu, W.J., and Chien, T.M. (2025). Risk Factors Predictive of Contralateral Recurrence of Upper Tract Urothelial Carcinoma Include Chronic Kidney Diseases and Postoperative Initiation of Dialysis. Cancers, 17.","DOI":"10.3390\/cancers17040664"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e3784","DOI":"10.1002\/dmrr.3784","article-title":"Comparison between sodium-glucose cotransporter 2 inhibitors and dipeptidyl peptidase 4 inhibitors on the risk of incident cancer in patients with diabetes mellitus: A real-world evidence study","volume":"40","author":"Sung","year":"2024","journal-title":"Diabetes\/Metab. Res. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s10654-024-01100-0","article-title":"Diabetes and the risk of bladder cancer subtypes in men and women: Results from the Netherlands Cohort Study","volume":"39","year":"2024","journal-title":"Eur. J. Epidemiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Andrew, A.S., Hu, T., Gu, J., Gui, J., Ye, Y., Marsit, C.J., Kelsey, K.T., Schned, A.R., Tanyos, S.A., and Pendleton, E.M. (2012). HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051301"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100964","DOI":"10.1016\/j.ajpc.2025.100964","article-title":"Composite socio-environmental risk score for cardiovascular assessment: An explainable machine learning approach","volume":"22","author":"Chen","year":"2025","journal-title":"Am. J. Prev. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.semcancer.2018.04.008","article-title":"Statistical methods for genome-wide association studies","volume":"55","author":"Wang","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_32","first-page":"1","article-title":"A Unified Approach to Interpreting Model Predictions","volume":"30","author":"Lundberg","year":"2017","journal-title":"Neural Inf. Process. Syst."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6378\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:03:13Z","timestamp":1760032993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6378"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,2]]},"references-count":32,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136378"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136378","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,7,2]]}}}