MTAP loss in gastrointestinal cancers is associated with CDKN2A deletion, poor prognosis in gastric carcinoma, and potential relevance for PRMT5-targeted therapy.

Gastrointestinal cancers account for a substantial share of global cancer burden. We assessed the significance of MTAP loss across 1545 resected tumors (cholangiocarcinoma, esophageal and gastric adenocarcinoma, pancreatic ductal adenocarcinoma). MTAP protein was evaluated by immunohistochemistry compared with CDKN2A status by fluorescence in situ hybridization and with overall survival. Immunohistochemical MTAP loss consistently co-occurred with homozygous CDKN2A deletion and was present in 25.5% of cholangiocarcinomas, 9.3% of esophageal adenocarcinomas, 10.3% of gastric carcinomas, and 30.2% of pancreatic adenocarcinomas. In gastric carcinomas, MTAP loss was associated with worse survival (p = 0.024), particularly in those who underwent primary surgery (p = 0.008). MTAP loss proved to be an independent factor for worse overall survival in patients with gastric adenocarcinoma. 10% of esophageal adenocarcinomas showed intratumoral heterogeneity, but we did not see intertumoral heterogeneity between the primary tumor and corresponding lymph node metastases. These data indicate that a considerable subset of gastrointestinal cancers exhibits MTAP loss, highlight prognostic relevance in gastric carcinoma, and delineate a potentially actionable subgroup for PRMT5 inhibitor therapy.