{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:47:01Z","timestamp":1788911221479,"version":"build-2803163510"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum Hamburg-Eppendorf (UKE)"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Complete expression loss of S-methyl-5\u2032-thioadenosine phosphorylase (<jats:italic>MTAP<\/jats:italic>) is caused by homozygous 9p21 deletion and results in a critical vulnerability of cancer cells towards drugs targeting multiple different pathways. MTAP deficiency is common in urothelial cancer, but data on its intratumoral heterogeneity\u2014a potential obstacle for targeted therapies\u2014are lacking. To study the heterogeneity of MTAP expression loss and 9p21 deletions in advanced primary urothelial cancers of the urinary bladder, a tissue microarray (TMA) composed of five different tissue spots from different tissue blocks of 105 pT2-4 urothelial carcinomas was analyzed by immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH). In addition, all tumor containing blocks (1\u201315, average 6.4) from 41 consecutive pT2-4 carcinomas were analyzed by IHC. Complete absence of MTAP staining (MTAP deficiency) was seen in 34.2% of 385 interpretable TMA samples. All 80 samples with a complete MTAP expression loss and FISH data had a homozygous 9p21 deletion while there were no cases with homozygous deletions within 178 samples with retained MTAP expression (100% FISH\/IHC concordance). On a patient level, there was a homogeneous MTAP deficiency in 33%, a heterogeneous MTAP deficiency in 1%, and a retained MTAP expression in 66% of the 98 tumors with at least three interpretable TMA samples. Among 41 consecutive pT2-4 carcinomas from which 1\u201315 (average 6.4) whole sections were analyzed, MTAP was homogeneously deficient in 34.1%, heterogeneously deficient in 4.9% and homogeneously retained in 61.0%. MTAP deficiency is mostly homogeneous in advanced urothelial carcinoma. MTAP IHC is a near perfect surrogate for the detection of homozygous 9p21 (<jats:italic>MTAP<\/jats:italic>) deletions. Drugs targeting MTAP deficiency could be highly useful in a relevant subset of invasive urothelial bladder cancers.<\/jats:p>","DOI":"10.1038\/s41598-025-10157-0","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T15:34:01Z","timestamp":1752593641000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["MTAP deficiency is highly homogeneous in advanced, muscle-invasive urothelial carcinoma of the urinary bladder"],"prefix":"10.1038","volume":"15","author":[{"given":"Natalia","family":"Gorbokon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Teljuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Reiswich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Lutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian Dwertmann","family":"Rico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"L\u00fchr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bernreuther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaryna Klos","family":"Al Bunni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosima","family":"V\u00f6lkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Plage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Lennartz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margit","family":"Fisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Minner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Simon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Sauter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zecha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Steurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Schlomm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatjana","family":"Vlajnic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Bubendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Kluth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Viehweger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morton","family":"Freytag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"10157_CR1","doi-asserted-by":"publisher","first-page":"12324","DOI":"10.1016\/S0021-9258(18)67242-4","volume":"261","author":"F Della Ragione","year":"1986","unstructured":"Della Ragione, F., Carteni-Farina, M., Gragnaniello, V., Schettino, M. 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Codeletion of the genes for p16INK4, methylthioadenosine phosphorylase, interferon-alpha1, interferon-beta1, and other 9p21 markers in human malignant cell lines. Cancer Genet. Cytogenet. 86, 22\u201328. https:\/\/doi.org\/10.1016\/0165-4608(95)00157-3 (1996).","journal-title":"Cancer Genet. Cytogenet."},{"key":"10157_CR4","doi-asserted-by":"publisher","first-page":"1797","DOI":"10.1038\/s41467-022-29397-z","volume":"13","author":"O Alhalabi","year":"2022","unstructured":"Alhalabi, O. et al. MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers. Nat. Commun. 13, 1797. https:\/\/doi.org\/10.1038\/s41467-022-29397-z (2022).","journal-title":"Nat. Commun."},{"key":"10157_CR5","doi-asserted-by":"publisher","first-page":"1264785","DOI":"10.3389\/fonc.2023.1264785","volume":"13","author":"C Bray","year":"2023","unstructured":"Bray, C., Balcells, C., McNeish, I. A. & Keun, H. C. 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Other authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The use of archived remnants of diagnostic tissues for manufacturing of TMAs and their analysis for research purposes as well as patient data analysis has been approved by local laws (HmbKHG, \u00a712) and by the local ethics committee (Ethical Committee of the Hamburg Medical Association, Hamburg, Germany; WF-049\/09). Informed consent was obtained from all subjects and\/or their legal guardian(s). All work has been carried out in compliance with the Helsinki Declaration.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}],"article-number":"25581"}}