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 clinicopathological 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, co-alterations, clinical outcomes, and therapeutic efficacy. In MONSTAR-SCREEN-2 (cohort B; n = 714), multiomic 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 blockers (ICB) treatment. In MTAP loss tumors, transcriptomic analyses of cohort B revealed reduced infiltration of T cells, while 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 co-deletion 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.

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Journal
Clinical Cancer Research
Published
2026-05-18
DOI
https://doi.org/10.1158/1078-0432.ccr-25-4936
Primary Topic
RNA modifications and cancer
Type
article
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article

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

Yu Oyama, Chigusa Morizane, Yoshiaki Nakamura, Sadakatsu Ikeda et al.
Clinical Cancer Research
RNA modifications and cancer
article

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

Yu Oyama, Chigusa Morizane, Yoshiaki Nakamura, Sadakatsu Ikeda, Kyosuke Seguchi, Hidemichi Watari, Kenjiro Namikawa, Eiji Oki, H Iwata, Susumu Okano, Norio Nonomura, Tomohiro Nishina, Satoshi Yuki, Shogen Boku, Naoki Takahashi, Makoto Ueno, Hideaki Bando, Shigenori Kadowaki, Tishihiro Kudo, Takao Fujisawa, Takayuki Yoshino, Wataru Yamagami
article en

Abstract

PURPOSE: Methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene, with loss of MTAP occurring in approximately 15% of solid tumors; however, its molecular and clinicopathological 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, co-alterations, clinical outcomes, and therapeutic efficacy. In MONSTAR-SCREEN-2 (cohort B; n = 714), multiomic 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 blockers (ICB) treatment. In MTAP loss tumors, transcriptomic analyses of cohort B revealed reduced infiltration of T cells, while 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 co-deletion 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.

Clinical Cancer Research
Osaka Gakuin University (JP), Tokyo Medical and Dental University (JP), Kansai Medical University (JP), Kyushu University (JP), Sapporo University (JP), Keio University (JP), Hokkaido University (JP), Kanagawa Prefectural Hospital Organization (JP), National Cancer Center (US), Keio University Hospital (JP), Kameda Medical Center (JP), Saitama Cancer Center (JP), Aichi Cancer Center (JP), Shikoku Cancer Center (JP), Hokkaido University Hospital (JP), National Cancer Center Hospital East (JP), Osaka International Cancer Institute (JP), Tokyo National Hospital (JP), National Cancer Research Institute (GB), The University of Osaka (JP)
Openalex Percentile: Top 8%
RNA modifications and cancer
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