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

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.

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.

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.

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.