Abstract 1046: Prevalence of MTAP deficiencyin human cancer: A tissue microarray study on 17,078 cancers from 149 different tumor types

Media type: E-Article

Title: Abstract 1046: Prevalence of MTAP deficiencyin human cancer: A tissue microarray study on 17,078 cancers from 149 different tumor types

Contributor: Gorbokon, Natalia; Lennartz, Maximilian; Hoeflmayer, Doris; Rico, Sebastian Dwertmann; Kind, Simon; Reiswich, Viktor; Viehweger, Florian; Lutz, Florian; Fraune, Christoph; Luebke, Andreas M.; Hube-Magg, Claudia; Büscheck, Franziska; Menz, Anne; Schlichter, Ria; Krech, Till; Hinsch, Andrea; Burandt, Eike; Sauter, Guido; Simon, Ronald; Steurer, Stefan; Marx, Andreas H.; Lebok, Patrick; Dum, David; Minner, Sarah; [...]

Published: American Association for Cancer Research (AACR), 2024

Language: English

DOI: 10.1158/1538-7445.am2024-1046

ISSN: 1538-7445

Keywords: Cancer Research ; Oncology

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Description: Abstract The S-methyl-5′-thioadenosine phosphorylase (MTAP) gene is located at 9p21 and is often co-deleted with CDKN2A. Because homozygous MTAP deletions result in a complete expression loss, MTAP immunohistochemistry (IHC) can be used for detection of homozygous deleted cells. MTAP IHC is of diagnostic utility for the distinction of mesotheliomas (often 9p21 deleted) from benign mesothelial proliferations. Moreover, evidence is emerging that MTAP deficiency results in a critical vulnerability of cancer cells towards drugs targeting several different pathways that depend on a functional MTAP gene and also causes resistance to immune checkpoint inhibitors. To determine the prevalence of complete MTAP expression loss and to assess the diagnostic utility of MTAP IHC, a tissue microarray containing 17,078 samples from 149 different tumor entities and 608 samples of 76 different normal tissue types was analyzed by IHC. All cases with complete MTAP loss were validated by fluorescence in situ hybridization (FISH). In normal tissues, MTAP was ubiquitously expressed resulting in a cytoplasmic and nuclear MTAP staining. At least one case with a complete MTAP expression loss was observed in 87 of 149 (58%) tumor categories. MTAP staining was most commonly lost in neuroendocrine neoplasms of various sites (up to 80%), Hodgkin’s lymphoma (38%), mesothelioma (24-30%), bilio-pancreatic adenocarcinomas (9-36%), urothelial neoplasms (19-29%), malignant melanoma (14-21%), mucinous carcinoma of the ovary (27%), squamous cell carcinomas of various organs of origin (up to 24%), various types of sarcomas (up to 20%), adenocarcinoma of the lung (11%), gastro-esophageal adenocarcinomas (2.6-11%), and in various types of non-Hodgkin’s lymphomas (up to 14%). FISH validation identified homozygous 9p21 deletions in 90-98% of cases with MTAP expression loss in most tumor categories including urothelial neoplasms, mesotheliomas, and pancreatic cancers, and others. There were, however, also tumor types such as neuroendocrine tumors and Hodgkin’s lymphomas that always lacked 9p21 deletions. In summary, our data provide a comprehensive overview on MTAP expression in cancer and show a strong link between MTAP expression loss and homozygous 9p21 deletions in most tumor entities. These cancers might most benefit from cancer drugs targeting MTAP deficiency. The absence of 9p21 deletions in other entities with frequent MTAP expression loss demonstrates that other mechanisms can cause significant MTAP downregulation. Whether these tumors benefit from targeting MTAT deficiency remains to be determined. Citation Format: Natalia Gorbokon, Maximilian Lennartz, Doris Hoeflmayer, Sebastian Dwertmann Rico, Simon Kind, Viktor Reiswich, Florian Viehweger, Florian Lutz, Christoph Fraune, Andreas M. Luebke, Claudia Hube-Magg, Franziska Büscheck, Anne Menz, Ria Schlichter, Till Krech, Andrea Hinsch, Eike Burandt, Guido Sauter, Ronald Simon, Stefan Steurer, Andreas H. Marx, Patrick Lebok, David Dum, Sarah Minner, Frank Jacobsen, Till S. Clauditz, Christian Bernreuther, Martina Kluth. Prevalence of MTAP deficiencyin human cancer: A tissue microarray study on 17,078 cancers from 149 different tumor types [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 1046.

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