Abstract 2654: MTAP deficiency is highly homogeneous in advanced, muscle-invasive urothelial carcinoma of the urinary bladder

Abstract Complete expression loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) 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 - a potential obstacle for targeted therapies - are 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) was constructed from 5 different sites from different tissue blocks of 105 pT2-4 urothelial carcinomas and analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). In addition, all 1-15 tumor containing blocks (average 6.1) from 41 consecutive pT2-4 carcinomas were analyzed by IHC. Complete absence of MTAP staining (MTAP deficiency) was seen in 132 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 148 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 these 98 tumors with at least 3 interpretable TMA samples. Among the 41 consecutive pT2-4 carcinomas from which whole sections were analyzed, MTAP was homogeneously deficient in 34%, heterogeneously deficient in 4.9% and homogeneously retained in 61%. It is concluded that MTAP deficiency is mostly homogeneous in advanced urothelial carcinoma. MTAP IHC is a near perfect surrogate for the detection of homozygous 9p21 (MTAP) deletions. Drugs targeting MTAP-deficiency could be highly useful in a relevant subset of invasive urothelial bladder cancers. Citation Format: Natalia Gorbokon, Viktor Reiswich, Florian Lutz, Sebastian Dwertmann Rico, Henning Plage, Maximilian Lennartz, Margit Fisch, Sarah Minner, Elena Bady, Lisa Hornsteiner, Ronald Simon, Guido Sauter, Henrik Zecha, Stefan Steurer, Thorsten Schlomm, Lukas Bubendorf, David Horst, Thorsten Ecke, Stefan Koch, Martina Kluth, Florian Viehweger, Morton Freytag. MTAP deficiency is highly homogeneous in advanced, muscle-invasive urothelial carcinoma of the urinary bladder [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2654.