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Prevalence of S-methyl-5'-thioadenosine Phosphorylase (MTAP) Deficiency in Human Cancer: A Tissue Microarray Study on

Natalia Gorbokon1, Niklas Wößner1, Maximilian Lennartz1

  • 1Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse, Hamburg, Germany.

The American Journal of Surgical Pathology
|August 12, 2024
PubMed

Insights

Loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression, a cancer vulnerability, occurs across many tumor types. MTAP deficiency is linked to poor prognosis and a noninflamed tumor microenvironment, not always deletions.

Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Pathology

Background:

  • Loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression is a frequent event in cancer.
  • This loss creates a vulnerability in cancer cells, making them susceptible to certain anti-cancer drugs.
  • Homozygous MTAP deletions are a primary cause of complete expression loss, detectable via immunohistochemistry (IHC).

Purpose of the Study:

  • To investigate the prevalence and diagnostic value of MTAP expression loss across a wide range of tumor entities.
  • To correlate MTAP deficiency with tumor phenotype, genetic alterations (deletions), and the tumor microenvironment.
  • To assess the utility of MTAP IHC in detecting neoplastic transformation.

Main Methods:

  • Analysis of a large tissue microarray (17,078 samples, 149 tumor entities) using immunohistochemistry (IHC) for MTAP expression.
  • Validation of complete MTAP loss using fluorescence in situ hybridization (FISH) to detect homozygous deletions.
  • Correlation of MTAP status with clinical data, including tumor phenotype, PD-L1 expression, and CD8+ lymphocyte density.

Main Results:

  • MTAP loss was identified in 83 out of 149 tumor categories, with high frequencies in neuroendocrine neoplasms (up to 80%), Hodgkin lymphoma (50%), and various adenocarcinomas and carcinomas.
  • Homozygous MTAP deletions accounted for 90-100% of MTAP loss in most tumor types, but were absent in neuroendocrine tumors, Hodgkin lymphoma, and other lymphomas.
  • MTAP deficiency correlated with unfavorable tumor phenotypes, increased PD-L1 on tumor cells, decreased PD-L1 on immune cells, and lower CD8+ T-cell density.

Conclusions:

  • MTAP deficiency is a widespread phenomenon in various cancers, not solely explained by homozygous deletions.
  • MTAP loss is associated with aggressive tumor characteristics and an immunosuppressive tumor microenvironment.
  • MTAP IHC serves as a valuable diagnostic tool for identifying neoplastic transformation across diverse applications.

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