Clinicogenomic Landscape of MTAP -Deleted Thoracic Malignancies Across US and Japanese Nationwide Cohorts: Impact of Concurrent CDKN2A Alterations and Driver Mutations

PURPOSE Methylthioadenosine phosphorylase ( MTAP ) deletion represents a promising therapeutic vulnerability through synthetic lethality. However, the clinical and molecular context of MTAP -deleted thoracic tumors, particularly with respect to actionable oncogenic drivers and immune checkpoint inhibitor efficacy, remains incompletely defined across diverse populations. METHODS We analyzed clinicogenomic data from two nationwide cohorts: AACR Project GENIE (United States; n = 11,091 evaluable samples) and Center for Cancer Genomics and Advanced Therapeutics (C-CAT; Japan; n = 4,851). MTAP copy number was assessed in lung, pleural, and thymic tumors. We evaluated histology-specific prevalence, comutational patterns, associations with actionable genomic alterations, tumor mutational burden (TMB), and overall survival (OS) in selected molecular subgroups. RESULTS In lung cancer, MTAP deletion occurred at comparable frequencies between adenocarcinoma and squamous cell carcinoma within each cohort (GENIE: 8.1% v 9.8%; C-CAT: 19.6% v 16.5%) but was rare in small cell lung cancer (GENIE: 1.0%; C-CAT: 1.9%). In thymic tumors, MTAP deletion was observed predominantly in thymic carcinoma and was uncommon in thymoma. MTAP deletion was strongly associated with CDKN2A/B deletions and was rare in their absence. MTAP deletion frequently coexisted with actionable driver alterations, including EGFR mutations, ALK fusions, and ERBB2 alterations. A robust inverse association with RB1 mutations was observed in both cohorts. Although MTAP deletion appeared associated with lower TMB ( P < .01) and shorter OS in EGFR -mutated lung cancer (median 18.5 v 31.4 months, P < .01), these associations were largely attributable to enrichment of oncogenic drivers and concurrent CDKN2A loss, respectively. CONCLUSION MTAP -deleted thoracic tumors exhibit reproducible clinical and molecular features across populations. Our findings support the rational, globally applicable development of MTAP -targeted synthetic lethal strategies in thoracic malignancies, particularly in combination with molecular targeted agents.