Abstract A028: MTAP deficiency is frequent and mostly homogeneous in ductal adenocarcinomas of the pancreas

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Abstract Complete expression loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) is caused by homozygous 9p21 deletion and results in a critical vulnerability of cancer cells towards drugs targeting multiple different pathways. MTAP deficiency is common in ductal adenocarcinoma of the pancreas, but data on its intratumoral heterogeneity - a potential obstacle for targeted therapies - are lacking. To learn more on the role and potential heterogeneity of MTAP deficiency in pancreatic adenocarcinoma, 236 primary tumors were analyzed in a tissue microarray (TMA) format by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for MTAP expression and 9p21 deletions. The cohort included 236 cancers from which 6 samples were taken from as many as possible different tumor containing primary tumor blocks and 3 samples were added from as many as possible lymph node metastases to construct a “heterogeneity TMA”. All available tumor containing blocks (average 4) from 6 selected cancers were also analyzed by IHC and FISH on whole sections. Complete absence of MTAP staining was seen in 350 (38.6%) of 907 interpretable TMA samples. 284 (98.6%) of 288 samples with a complete MTAP expression loss and FISH data had a homozygous 9p21 deletion while there were only two tumor spots with homozygous deletions within 557 samples with retained MTAP expression (99.6% concordance). On a patient level, an MTAP deficiency was found in 64 (41.0%) of 156 tumors for which at least 3 different samples were interpretable on the TMAs. 62 (96.9%) of these patients showed an MTAP loss in all interpretable samples (homogeneous MTAP deficiency). The TMA data were confirmed on whole sections in 5 of 6 patients. In the discrepant case a focal MTAP loss was identified in a tumor considered MTAP wild type based on the TMA results. It is concluded that MTAP expression loss is frequent and highly homogeneous in ductal adenocarcinomas of the pancreas. Given the high concordance rate between homozygous deletion and MTAP expression loss homozygous deletion may represent the only mechanism for MTAP deficiency in pancreatic cancer. MTAP IHC is an excellent tool for identification of MTPA deficient cases. MTAP IHC may also have considerable diagnostic value as even low-grade cancer glands can be easily identified in small biopsies from MTAP deficient cases. 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. Citation Format: Natalia Gorbokon, Katharina Teljuk, Frank Jacobsen, Till Krech, Till Clauditz, Stefan Steurer, Ronald Simon, Guido Sauter, Sarah Minner, Lukas Bubendorf, Thilo Hackert, Nina Schraps, Faik G Uzunoglu, Martina Kluth. MTAP deficiency is frequent and mostly homogeneous in ductal adenocarcinomas of the pancreas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A028.