Pan-cancer clinical and molecular landscape of MTAP deletion in nationwide and international comprehensive genomic data

BACKGROUND: Early-phase clinical trials of protein arginine methyltransferase 5 (PRMT5) inhibitors as synthetic lethal strategies have shown promising efficacy in methylthioadenosine phosphorylase (MTAP)-deleted tumors. To refine and expand this promising therapeutic approach within the framework of precision oncology, it is critical to comprehensively characterize the clinical and molecular profiles of MTAP-deleted tumors. MATERIALS AND METHODS: This pan-cancer retrospective cohort study analyzed clinico-genomic data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, which includes 99.7% of patients who underwent comprehensive genomic profiling (CGP) in Japan between June 2019 and November 2023. Machine learning and explainable artificial intelligence methods were applied to identify clinical predictors of MTAP deficiency. Findings were validated and compared using The Cancer Genome Atlas (TCGA) and American Association for Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE) datasets. RESULTS: Among 51 828 pan-cancer patients in the C-CAT cohort, MTAP deletion was observed in 4964 cases (9.6%), with a high prevalence in pancreatic (18.4%), biliary tract (15.6%), and lung (14.3%) cancers. MTAP deletion was associated with distinct clinical features, including male sex (56.0% versus 47.8%), older age (mean 62.4 versus 59.8 years), and shorter interval from diagnosis to CGP (median 380.0 versus 567.0 days). In pancreatic cancer, MTAP deletion was more common in KRAS-mutant tumors (19.8%) compared with KRAS wild-type tumors (8.9%). Across cancer types, MTAP deletion was less frequent in RB1-mutant tumors (pan-cancer: 3.2%, pancreatic: 7.6%, lung: 2.5%, biliary tract: 5.4%) than in RB1 wild-type tumors (9.9%, 18.7%, 16.1%, 16.0%). These findings were validated using the TCGA (n = 9896) and GENIE (n = 178 034) datasets. In lung adenocarcinoma, MTAP deletion was found in 22.8% of EGFR-mutated tumors, 25.0% of ALK-translocated tumors, and 20.8% of ROS1-translocated tumors. CONCLUSIONS: MTAP deletion is associated with unique clinical and molecular features. These findings define the characteristics of MTAP-deleted cancers and provide a basis for synthetic lethal strategies in precision oncology.