Prevalence of S-methyl-5'-thioadenosine Phosphorylase (MTAP) Deficiency in Human Cancer: A Tissue Microarray Study on 13,067 Tumors From 149 Different Tumor Types

Our plain-English summary of Prevalence of S-methyl-5'-thioadenosine Phosphorylase (MTAP) Deficiency in Human Cancer: A Tissue Microarray Study on 13,067 Tumors From 149 Different Tumor Types, by N. Gorbokon, N. Wößner, M. Lennartz, et al (The American Journal of Surgical Pathology, 2024).

The study

• Authors: N. Gorbokon, N. Wößner, M. Lennartz, S. Dwertmann Rico, S. Kind, V. Reiswich, F. Viehweger, F. Lutz, C. Fraune, A.M. Luebke, C. Hube-Magg, A. Menz, R. Schlichter, T. Krech, A. Hinsch, E. Burandt, G. Sauter, R. Simon, S. Steurer, A.H. Marx, P. Lebok, D. Dum, S. Minner, F. Jacobsen, T.S. Clauditz, T. Hackert, F.G. Uzunoǧlu, L. Bubendorf, C. Bernreuther, M. Kluth
• Journal: The American Journal of Surgical Pathology
• Published: 2024;48(10):1245-1258
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression is a common event in cancer leading to a critical vulnerability of cancer cells towards anti-cancer drugs. Homozygous MTAP deletions result in a complete expression loss that can be detected by immunohistochemistry (IHC). In this study, a tissue microarray containing 17,078 samples from 149 different tumor entities was analyzed by IHC, and complete MTAP loss was validated by fluorescence in situ hybridization. MTAP loss was observed in 83 of 149 tumor categories, including neuroendocrine neoplasms (up to 80%), Hodgkin lymphoma (50.0%), mesothelioma (32.0% to 36.8%), gastro-intestinal adenocarcinoma (4.0% to 40.5%), urothelial neoplasms (10.5% to 36.7%), squamous cell carcinomas (up to 38%), and various types of sarcomas (up to 20%) and non-Hodgkin lymphomas (up to 14%). Homozygous MTAP deletion was found in 90% to 100% of cases with MTAP expression loss in most tumor categories. However, neuroendocrine tumors, Hodgkin lymphomas, and other lymphomas lacked MTAP deletions. MTAP deficiency was significantly linked to unfavorable tumor phenotype in selected tumor entities and the presence of PD-L1 expression on tumor cells, absence of PD-L1 expression on immune cells, and a low density of CD8 + lymphocytes. In summary, MTAP deficiency can occur in various tumor entities and is linked to unfavorable tumor phenotype and noninflamed tumor microenvironment, but is not always related to deletions. MTAP IHC is of considerable diagnostic value for the detection of neoplastic transformation in multiple different applications.

Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.

In plain English

This laboratory study did not examine asbestos exposure. Using staining on tissue microarrays, it tested archived German tumor samples for complete loss of the protein MTAP. Each tumor with complete loss was also tested with FISH for a deletion in chromosome region 9p21, which holds the MTAP and CDKN2A genes. Of 17,078 tumor samples from 149 tumor types, 13,067 could be interpreted. Complete MTAP loss was seen in 933 (7.1%) tumors, with at least one case in 83 of 149 categories. Loss was found in 32.0% of epithelioid mesotheliomas (25 analyzable) and 36.8% of biphasic mesotheliomas (19 analyzable). Staining and FISH agreed in 100% of mesotheliomas with loss. In Hodgkin lymphoma, other lymphomas and neuroendocrine tumors, loss mostly occurred without a deletion. Pooling the tumor subsets with immune data from an earlier study, MTAP-deficient tumors more often had PD-L1-positive tumor cells, less often PD-L1-positive immune cells, and fewer CD8+ cells. The authors concluded that their mesothelioma results support using MTAP staining to distinguish malignant mesothelioma from benign mesothelial conditions. They noted that staining and FISH were not done on consecutive tissue sections.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Tissue microarray study of archived tumor samples using MTAP immunohistochemistry, with FISH validation of all tumors showing complete MTAP loss
• Who was studied: 17,078 primary tumors from 149 tumor types, of which 13,067 (76.5%) were interpretable. Samples came from pathology archives in Hamburg, Osnabrueck and Fuerth, Germany. Mesothelioma: 40 epithelioid (25 analyzable) and 29 biphasic (19 analyzable). No dates of collection are given.
• Exposure: No asbestos or other exposure was studied. The study measured MTAP protein loss in tumor tissue and deletion of the chromosome 9p21 region, which contains the MTAP and CDKN2A genes.
• Main results:
  • Across all interpretable tumors, complete MTAP loss was seen in 933 (7.1%).
  • At least one case with complete MTAP loss occurred in 83 (55.7%) of the 149 tumor categories.
  • Complete MTAP loss was found in 32.0% of epithelioid mesotheliomas (25 analyzable) and 36.8% of biphasic mesotheliomas (19 analyzable).
  • In mesothelioma, MTAP staining and FISH agreed in 100% of tumors with MTAP loss.
  • Hodgkin lymphoma, several other lymphoma types, neuroendocrine tumors and neuroendocrine carcinomas often lost MTAP but almost completely lacked 9p21 deletions.
  • When neuroendocrine and hematological tumors were excluded, a homozygous 9p21 deletion was present in 96.7% of tumors with complete MTAP loss.
  • PD-L1 and CD8+ data came from a previous study and were available only for subsets of tumors. The results were pooled across tumor types. Tumors with MTAP loss more often had PD-L1-positive tumor cells (19.9% of 559 vs 15.7% of 7262 with retained MTAP, P = 0.0125). They less often had PD-L1-positive immune cells (61.9% vs 71.8%, P = 0.0008). They also had a lower mean CD8+ cell density (179.2 vs 263.3 cells/mm2, P = 0.0042).
• The authors' conclusion: The authors concluded that MTAP loss in their mesotheliomas supports the established role of MTAP staining for telling malignant mesothelioma apart from benign mesothelial conditions. More broadly, they concluded that MTAP staining is a diagnostic marker of neoplastic transformation.
• Limitations the authors state:
  • Staining and FISH were not done on consecutive tissue sections, so small groups of MTAP-deficient tumor cells may not have been present on the FISH sections. This could explain some cases where staining and FISH disagreed.
  • The comparison antibody 2G4 cross-reacted with mucus-producing goblet cells. The authors could not exclude that this cross-reactivity may hide MTAP loss in some mucus-producing tumors.

Topics

Medical terms in this study, explained in our Lexicon: MTAP, Immunohistochemistry, Fluorescence In Situ Hybridization (FISH), Neoplasm, Mesothelioma, Adenocarcinoma, Squamous Cell Carcinoma, Sarcoma.

Related studies

• Prevalence of heterozygous and homozygous 9p21 deletions in human cancer: a tissue microarray study on 4,999 tumors from 125 different tumor types — N. Gorbokon, K. Teljuk, et al. (2026)
• Reduced occludin expression is related to unfavorable tumor phenotype and poor prognosis in many different tumor types: A tissue microarray study on 16,870 tumors — S. Büyücek, F. Viehweger, et al. (2025)
• Stimulator of Interferon Genes Protein (STING) Expression in Cancer Cells: A Tissue Microarray Study Evaluating More than 18,000 Tumors from 139 Different Tumor Entities — A. Menz, J. Zerneke, et al. (2024)
• L1CAM/CD171 expression in human tumors and its association with tumor phenotype — S. Büyücek, M. Lurati, et al. (2025)
• Expression of Annexin A4 in Cancer: A Tissue Microarray Study Involving More than 17,600 Cancers from 148 Tumor Entities — C. Völkel, N. Malas, et al. (2026)
• Mesothelin Expression in Human Tumors: A Tissue Microarray Study on 12,679 Tumors — S. Weidemann, P. Gagelmann, et al. (2021)

Browse more research in The American Journal of Surgical Pathology, or return to medical research.