{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:51:40Z","timestamp":1787014300228,"version":"build-2736575974"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2025,2]]},"abstract":"\n Aims<\/jats:title>\n \n Loss of heterozygosity in chromosome 9p21, common in urothelial carcinoma (UC), typically involves deletion of\n CDKN2A<\/jats:italic>\n and\n MTAP<\/jats:italic>\n genes. MTAP loss is emerging as a promising therapeutic target and predictive biomarker in UC. This single\u2010centrre retrospective study examined the incidence of\n CDKN2A<\/jats:italic>\n deletions and MTAP loss in muscle\u2010invasive bladder cancer (MIBC) and metastatic urothelial carcinoma (mUC), investigating their correlations with clinical, pathological, and genomic features, as well as patient outcomes.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Fluorescence\n in situ<\/jats:italic>\n hybridization (FISH) and immunohistochemistry (IHC) were performed on 302 MIBC specimens and 63 biopsy\u2010proven metachronous urothelial metastases to assess\n CDKN2A<\/jats:italic>\n deletions and MTAP protein expression.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n CDKN2A<\/jats:italic>\n homozygous deletion (HD), identified in 30.3% of MIBCs, and MTAP loss, found in 28.8% of MIBCs, were both significantly associated with the luminal\u2010URO subtype,\n FGFR3<\/jats:italic>\n mutations, and normal\/wildtype p53 IHC (\n P<\/jats:italic>\n \u2009<\u20090.05). Loss of MTAP expression was significantly correlated with\n CDKN2A<\/jats:italic>\n HD, with 84.0% sensitivity, 92.3% negative predictive value (NPV), 96.3% specificity, and 91.9% positive predictive value (PPV). MTAP expression was 100% concordant between primary tumours and nodal metastases. Patients with MTAP loss had a higher incidence of visceral metastases (50%) compared to bone\/soft tissue (35.7%) and nodes (14.3%). Mean progression\u2010free survival and overall survival were shorter for patients with MTAP loss, although not statistically significant.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Our findings highlight\n CDKN2A<\/jats:italic>\n HD and MTAP loss as prevalent genetic alterations in MIBC and mUC, particularly within the luminal\u2010URO subtype and\n FGFR3<\/jats:italic>\n \u2010mutated, p53\u2010normal\/wildtype tumours. MTAP IHC can serve as a surrogate marker for 9p21.3 HD, highlighting its clinical relevance and potential as a therapeutic target and predictive biomarker in MIBC.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/his.15324","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T02:55:20Z","timestamp":1727405720000},"page":"352-364","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["MTAP protein status is highly concordant with\n CDKN2A<\/i>\n fluorescent\n in situ<\/i>\n hybridization and allows stratification of the luminal subtype in muscle\u2010invasive bladder cancer"],"prefix":"10.1111","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7945-7801","authenticated-orcid":false,"given":"Ekaterina","family":"Olkhov\u2010Mitsel","sequence":"first","affiliation":[{"name":"Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Precision Diagnostics and Therapeutics Program Sunnybrook Health Sciences Centre Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5024-7974","authenticated-orcid":false,"given":"Alexander","family":"Oberc","sequence":"additional","affiliation":[{"name":"Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Precision Diagnostics and Therapeutics Program Sunnybrook Health Sciences Centre Toronto ON Canada"},{"name":"Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9702-0830","authenticated-orcid":false,"given":"Kenneth J","family":"Craddock","sequence":"additional","affiliation":[{"name":"Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Precision Diagnostics and Therapeutics Program Sunnybrook Health Sciences Centre Toronto ON Canada"},{"name":"Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Sherman","sequence":"additional","affiliation":[{"name":"Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Precision Diagnostics and Therapeutics Program Sunnybrook Health Sciences Centre Toronto ON Canada"},{"name":"Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elzbieta","family":"Slodkowska","sequence":"additional","affiliation":[{"name":"Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Precision Diagnostics and Therapeutics Program Sunnybrook Health Sciences Centre Toronto ON Canada"},{"name":"Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4528-3724","authenticated-orcid":false,"given":"Michelle R","family":"Downes","sequence":"additional","affiliation":[{"name":"Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Precision Diagnostics and Therapeutics Program Sunnybrook Health Sciences Centre Toronto ON Canada"},{"name":"Laboratory Medicine and Pathobiology University of Toronto Toronto ON 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