Comprehensive Genomic and Transcriptomic Characterization of MTAP Loss across Advanced Solid Tumors

PURPOSE: Methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene, with loss of MTAP occurring in approximately 15% of solid tumors; however, its molecular and clinicopathologic significance remains incompletely defined. EXPERIMENTAL DESIGN: We conducted a multicenter observational study using two nationwide Japanese genomic screening programs, defining MTAP loss as homozygous deletion. In the MONSTAR-SCREEN-1 study (cohort A; n = 773), patients underwent tissue-based next-generation sequencing to evaluate MTAP status, coalterations, clinical outcomes, and therapeutic efficacy. In MONSTAR-SCREEN-2 (cohort B; n = 714), multiomics analyses were conducted using whole-exome and whole-transcriptome sequencing, including xCell immune deconvolution and gene set enrichment analysis (GSEA), to characterize the tumor immune microenvironment and signaling pathways associated with MTAP loss. RESULTS: Among 764 patients in cohort A, MTAP loss was identified in 71 cases. MTAP loss strongly co-occurred with CDKN2A/B deletions and was associated with lower tumor mutational burden and microsatellite stable status. Patients with MTAP loss had significantly shorter overall and progression-free survival under immune checkpoint blocker (ICB) treatment. In MTAP loss tumors, transcriptomic analyses of cohort B revealed reduced infiltration of T cells, whereas GSEA showed enrichment of cell cycle, RNA processing, and DNA repair pathways, and depletion of immune-related and metabolic pathways. CONCLUSIONS: MTAP loss defines a clinically adverse subset across advanced solid tumors, characterized by codeletion of CDKN2A/B and type I interferon cluster genes, reduced T-cell infiltration, and resistance to ICB. These findings provide a mechanistic context for ICB resistance.