Deletion of the 9p21 chromosomal region is among the most frequently observed homozygous genomic events in human cancers. This locus contains the methylthioadenosine phosphorylase (MTAP) gene along with CDKN2A and CDKN2B, and its loss has been associated with inferior clinical outcomes and diminished benefit from immune checkpoint blockade. Recent therapeutic strategies have highlighted MTAP deficiency as a targetable vulnerability through synthetic lethal interactions involving MAT2A and PRMT5 inhibition. The present study was designed to determine the incidence of MTAP loss across advanced gastrointestinal (GI) malignancies, characterize its accompanying genomic features, and evaluate its relevance as a prognostic biomarker. Comprehensive next-generation sequencing was conducted on a large dataset comprising 64,860 tumor specimens derived from five distinct GI cancer types. Integrated genomic and clinical analyses were performed, and patient outcomes were retrospectively compared between tumors harboring MTAP loss and those retaining MTAP. Across all GI cancers examined, MTAP loss was detected in 8.30% of cases. The alteration was most frequently observed in pancreatic ductal adenocarcinoma (PDAC), affecting 21.7% of tumors, while colorectal carcinoma (CRC) exhibited the lowest frequency at 1.1%. A higher proportion of MTAP-deficient tumors was identified among East Asian patients with PDAC (4.4% vs 3.2%, P = .005) and intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, P = .036). The presence of MTAP loss was associated with tumor type–specific differences in the distribution of potentially actionable genomic alterations, including ATM, BRAF, BRCA2, ERBB2, IDH1, PIK3CA, and PTEN. In PDAC, IHCC, and CRC, MTAP-deficient tumors demonstrated lower rates of microsatellite instability and reduced tumor mutational burden. Furthermore, tumor cell PD-L1 expression was less commonly observed in MTAP-loss IHCC compared with MTAP-intact counterparts (23.2% vs 31.2%, P = .017).MTAP deficiency in gastrointestinal cancers predominantly arises in conjunction with deletion of the 9p21 locus and is present in approximately 8% of cases overall. The frequency of MTAP loss varies considerably by tumor subtype, occurring in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC. Importantly, MTAP loss does not preclude the coexistence of other clinically relevant, targetable genomic alterations.
