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

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.

FIGURE 1

MTAP immunostaining of normal tissues. The panels show MTAP immunostaining of variable intensity for almost every cell type in each tissue. MTAP staining was particularly intense in interfollicular lymphocytes of a lymph node (A), urothelial cells in the urinary bladder (B), and in cytotrophoblast cells of the placenta (C). A moderate to strong MTAP staining was also seen in myometrium cells of the uterus (D), tubular cells of the kidney (E), and in spermatogonia and Leydig cells of the testis (F). MTAP staining was only weak in maturing spermatids of the testis (F), hepatocytes of the liver (G), and in colorectal epithelial cells (H).

FIGURE 2

MTAP loss in tumors lacking 9p21 deletion. MTAP staining was completely absent in tumor cells of a NET of the lung (A), a NET of the ileum (B), a colorectal NET (C), a pancreatic NET (D), a T-cell non-Hodgkin lymphoma (E), a marginal cell lymphoma (F) and in 2 cases of Hodgkin lymphoma (G and H). Distinct MTAP positivity of intermingled stroma cells serves as a positive internal control.

FIGURE 3

MTAP loss in tumors with homozygous 9p21 deletion. MTAP staining was completely lacking in tumor cells of an (epithelioid) malignant mesothelioma (A), a urothelial carcinoma of the renal pelvis (B), a mucinous ovarian carcinoma (C), a serous high-grade ovarian carcinoma (D), a malignant melanoma (E), a recurrent adenocarcinoma of the prostate (F), a colorectal adenocarcinoma (G), and a ductal adenocarcinoma of the pancreas (H). Distinct MTAP positivity of intermingled stroma cells and of non-neoplastic epithelial cells serves as a positive internal control.

FIGURE 4

Concordance rate of MTAP IHC and 9p21 copy number analysis.