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

<jats:p>&lt;div&gt;Abstract Purpose:&lt;p&gt;Methylthioadenosine phosphorylase (&lt;i&gt;MTAP&lt;/i&gt;) is a tumor suppressor gene, with loss of &lt;i&gt;MTAP&lt;/i&gt; occurring in approximately 15% of solid tumors; however, its molecular and clinicopathologic significance remains incompletely defined.&lt;/p&gt; Experimental Design:&lt;p&gt;We conducted a multicenter observational study using two nationwide Japanese genomic screening programs, defining &lt;i&gt;MTAP&lt;/i&gt; loss as homozygous deletion. In the MONSTAR-SCREEN-1 study (cohort A; &lt;i&gt;n&lt;/i&gt; = 773), patients underwent tissue-based next-generation sequencing to evaluate &lt;i&gt;MTAP&lt;/i&gt; status, coalterations, clinical outcomes, and therapeutic efficacy. In MONSTAR-SCREEN-2 (cohort B; &lt;i&gt;n&lt;/i&gt; = 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 &lt;i&gt;MTAP&lt;/i&gt; loss.&lt;/p&gt; Results:&lt;p&gt;Among 764 patients in cohort A, &lt;i&gt;MTAP&lt;/i&gt; loss was identified in 71 cases. &lt;i&gt;MTAP&lt;/i&gt; loss strongly co-occurred with &lt;i&gt;CDKN2A/B&lt;/i&gt; deletions and was associated with lower tumor mutational burden and microsatellite stable status. Patients with &lt;i&gt;MTAP&lt;/i&gt; loss had significantly shorter overall and progression-free survival under immune checkpoint blocker (ICB) treatment. In &lt;i&gt;MTAP&lt;/i&gt; 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.&lt;/p&gt; Conclusions:&lt;p&gt;&lt;i&gt;MTAP&lt;/i&gt; loss defines a clinically adverse subset across advanced solid tumors, characterized by codeletion of &lt;i&gt;CDKN2A/B&lt;/i&gt; and type I interferon cluster genes, reduced T-cell infiltration, and resistance to ICB. These findings provide a mechanistic context for ICB resistance.&lt;/p&gt;&lt;/div&gt;</jats:p>