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Updated: May 19, 2026
08:16
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Comprehensive Genomic and Transcriptomic Characterization of MTAP Loss across Advanced Solid Tumors
Kyosuke Seguchi1,2, Takao Fujisawa3,4, Sadakatsu Ikeda5
1Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Summary
Loss of the MTAP gene in solid tumors is linked to poorer survival and resistance to immune checkpoint blockers (ICB). This MTAP loss is associated with specific genetic changes and a less inflamed tumor microenvironment, explaining ICB treatment failure.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene frequently lost in solid tumors.
- The precise molecular and clinical impact of MTAP loss remains incompletely understood.
Purpose of the Study:
- To define the molecular and clinicopathological significance of MTAP loss in advanced solid tumors.
- To investigate the association between MTAP loss and clinical outcomes, particularly response to immune checkpoint blockers (ICB).
Main Methods:
- A multicenter observational study utilizing two Japanese nationwide genomic screening programs (MONSTAR-SCREEN-1 and MONSTAR-SCREEN-2).
- Tissue-based next-generation sequencing (NGS) for MTAP status and co-alterations.
- Multiomic analyses including whole exome/transcriptome sequencing, immune deconvolution (xCell), and gene set enrichment analysis (GSEA) to characterize the tumor immune microenvironment and pathways.
Main Results:
- MTAP loss was identified in 9.3% of patients and strongly co-occurred with CDKN2A/B deletions.
- MTAP loss was associated with lower tumor mutational burden, microsatellite stability, and significantly shorter overall and progression-free survival under ICB treatment.
- Transcriptomic analysis revealed reduced T-cell infiltration and enrichment of cell-cycle, RNA-processing, and DNA repair pathways, alongside depletion of immune-related and metabolic pathways in MTAP-loss tumors.
Conclusions:
- MTAP loss identifies a clinically adverse subset of advanced solid tumors.
- This subset is characterized by CDKN2A/B co-deletion, reduced T-cell infiltration, and resistance to ICB therapy.
- These findings offer a mechanistic explanation for ICB resistance in MTAP-loss tumors.
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