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Deficiency of MTAP Is Frequent and Mostly Homogeneous in Pancreatic Ductal Adenocarcinomas
Natalia Gorbokon1, Katharina Teljuk1, Viktor Reiswich1
1Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Background:
The complete loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression, often due to homozygous 9p21 deletion, creates a druggable vulnerability in cancer cells.
Methods:
A total of 769 primary pancreatic ductal adenocarcinomas were analyzed on tissue microarrays with MTAP immunohistochemistry (IHC) and 9p21 fluorescence in situ hybridization (FISH). Intratumoral heterogeneity was assessed on a "heterogeneity" TMA containing up to nine samples from different areas of 236 primary tumor and nodal metastases, and whole sections of all tumor blocks from 19 cancers.
Results:
MTAP expression loss was found in 181 (37.9%) of 478 interpretable primary tumors and was unrelated to pT, pN, grade, and tumor size. MTAP expression loss was homogenous in 37.6% and heterogeneous in 1.1% of the 181 tumors, with at least three evaluable samples on the heterogeneity TMA. On whole sections, 1 of 19 tumors showed heterogeneous MTAP loss. The correlation between IHC and FISH was nearly perfect, with 98.8% of MTAP-deficient samples showing a 9p21 deletion.
Conclusions:
MTAP expression loss is frequent, caused by homozygous deletion, and mostly homogeneous in pancreatic ductal adenocarcinomas. Considering also their aggressive clinical behavior, pancreatic adenocarcinomas may represent an ideal cancer type for studying new drugs targeting MTAP-deficient cancer cells in clinical trials.
Insights
Loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression is common in pancreatic cancer due to 9p21 deletions. This MTAP deficiency presents a potential therapeutic target for new cancer drugs.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- S-methyl-5'-thioadenosine phosphorylase (MTAP) expression loss, often from 9p21 deletion, creates a vulnerability in cancer cells.
- This vulnerability is targetable with specific cancer drugs.
Purpose of the Study:
- To investigate the frequency and characteristics of MTAP expression loss in pancreatic ductal adenocarcinomas.
- To assess the homogeneity of MTAP loss and its correlation with 9p21 deletions.
Main Methods:
- Analysis of 769 pancreatic ductal adenocarcinomas using tissue microarrays, MTAP immunohistochemistry (IHC), and 9p21 fluorescence in situ hybridization (FISH).
- Assessment of intratumoral heterogeneity on specialized TMAs and whole tumor sections.
Main Results:
- MTAP expression loss was observed in 37.9% of tumors and was not associated with tumor stage, grade, or size.
- MTAP loss was predominantly homogeneous (37.6%) rather than heterogeneous (1.1%).
- A strong correlation (98.8%) was found between MTAP deficiency and 9p21 deletion.
Conclusions:
- MTAP expression loss is a frequent and largely homogeneous event in pancreatic ductal adenocarcinomas, driven by homozygous deletion.
- The high frequency and aggressive nature of these tumors make them suitable for clinical trials targeting MTAP-deficient cells.
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