Abstract 1048: Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype and non-inflamed microenvironment in urothelial bladder cancer
Authors: Gorbokon Natalia , Wößner Niklas , Ahlburg Viktoria , Schallenberg Simon , Plage Henning , Hofbauer Sebastian , Furlano Kira , Weinberger Sarah , Bruch Paul G. , Roßner Florian , Elezkurtaj Sefer , Lennartz Maximilian , Blessin Niclas C. , Marx Andreas H. , Samtleben Henrik , Fisch Margit , Rink Michael , Slojewski Marcin , Kaczmarek Krystian , Ecke Thorsten , Hallmann Steffen , Koch Stefan , Adamini Nico , Minner Sarah , Simon Ronald , Sauter Guido , Zecha Henrik , Horst David , Klatte Tobias , Schlomm Thorsten , Kluth Martina 
Published: March 2024

Abstract
9p21 deletions are common in urothelial carcinoma and mostly include S-methyl-5′-thioadenosine phosphorylase (MTAP) a critical enzyme for DNA and RNA synthesis. Homozygous MTAP deletions result in a complete loss of expression which can be visualized by immunohistochemistry (IHC). Evidence is emerging that MTAP deficiency results in a critical vulnerability of cancer cells towards drugs targeting multiple different pathways that depend on a functional MTAP gene and causes resistance to immune checkpoint inhibitors. To determine the prevalence and clinical significance of MTAP deficiency and its relationship with the tumor microenvironment in urothelial bladder carcinomas, more than 2,500 tumors were analyzed by fluorescence in-situ hybridization (FISH) and IHC in a tissue microarray format, and the data were compared with existing data on intratumoral lymphocyte subsets and PD-L1 expression. The cohort included 1,826 patients that underwent radical cystectomy for muscle-invasive disease (pT2-4). 9p21 deletion was homozygous in 364 (21.3%) and heterozygous in 334 (19.5%) of 1,711 analyzable tumors. The rate of 9p21 deleted tumors increased from pTa G2 low (9.2% homozygous, 25.8% heterozygous) to pTa G2 high (32.6%, 20.9%; p&lt;0.0001) but was slightly lower in pTa G3 (16.7% each). In pT2-pT4 carcinomas, 9p21 deletions were homozygous in 23.3% and heterozygous in 17.9%. Within muscle-invasive cancers, 9p21 deletions were tied to high pT (p=0.0014) and poor overall survival (p=0.0461). MTAP expression loss was strongly linked to homozygous 9p21 deletions. Complete absence of MTAP staining was seen in 96.1% of homozygous deleted cancers while only 4 of 249 MTAP negative cancers had retained at least one 9p21 copy (p&lt;0.0001). Accordingly, absence of MTAP staining was also linked to advanced pT status and poor overall survival (p&lt;0.05 each). Tumors with heterozygous 9p21 deletion did often show preserved but low-level expression of MTAP. 9p21 deletions were associated with low numbers of PD-L1 positive tumor cells (p&lt;0.0001), CD8 (p=0.01) and CD4 positive lymphocytes (p=0.009), M2-macrophages (p&lt;0.0001), and dendritic cells (p=0.0007). A similar tendency was observed for MTAP expression loss, but the level of significance was only reached for PD-L1 positive tumor cells (p&lt;0.0001), M2 macrophages (p=0.001) and dendritic cells (p=0.012). Complete MTAP expression loss is common in urinary bladder cancer and strongly tied to homozygous 9p21 loss, aggressive disease, and non-inflamed microenvironment. Drugs targeting MTAP-deficiency may be highly useful in bladder cancer. MTAP IHC is an excellent surrogate for the detection of MTAP deficiency in this tumor entity.
Citation Format: Natalia Gorbokon, Niklas Wößner, Viktoria Ahlburg, Simon Schallenberg, Henning Plage, Sebastian Hofbauer, Kira Furlano, Sarah Weinberger, Paul G. Bruch, Florian Roßner, Sefer Elezkurtaj, Maximilian Lennartz, Niclas C. Blessin, Andreas H. Marx, Henrik Samtleben, Margit Fisch, Michael Rink, Marcin Slojewski, Krystian Kaczmarek, Thorsten Ecke, Steffen Hallmann, Stefan Koch, Nico Adamini, Sarah Minner, Ronald Simon, Guido Sauter, Henrik Zecha, David Horst, Tobias Klatte, Thorsten Schlomm, Martina Kluth. Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype and non-inflamed microenvironment in urothelial bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1048.