MTAP is a key gene involved in regulating methionine salvage pathway and polyamine metabolism. At ESMO 2024, we reported that MTAP loss was associated with prognosis and shorter progression of overall survival and immune checkpoint inhibitors. However, underlying biological mechanisms remain unclear. Herein, we present updated clinical outcomes together with transcriptomic analysis to illustrate these mechanisms...
MTAP is a key gene involved in regulating methionine salvage pathway and polyamine metabolism. At ESMO 2024, we reported that MTAP loss was associated with prognosis and shorter progression of overall survival and immune checkpoint inhibitors. However, underlying biological mechanisms remain unclear. Herein, we present updated clinical outcomes together with transcriptomic analysis to illustrate these mechanisms. We analyze patients with advanced tumors from Scrum Japan Monster Screen 1 and 2 study, a nationwide Match Center and genomic screening programs using tissue-based next-generation sequencing. Cohort A consisted of 773 patients enrolled in MONSTER-1 study, of whom 91 patients had MTAP loss with a prevalence of 9.2%. In this cohort, clinical outcomes and treatment efficacy were analyzed, and the FoundationOne CDx assay was performed. Cohort 2 consisted of 714 patients enrolled in MONSTER-2 study, of whom 64 patients had MTAP loss with a prevalence of 9.0%. In this cohort, transcriptomic data analyzed by KERIS-MI2-mutative hybrid was used for deconvolution and gene-set enrichment analysis and the next frequency of the pros across various cancer types in code and m, the plus a pancreatic ductal carcinoma has the highest frequency of MTAP loss, observed in 30.1% of cases, followed by urothelial carcinoma, virage tract cancer, melanoma, and gastric cancer. Whereas in cohort B, urothelial carcinoma has the highest frequency, observed in 36.1% of cases, followed by pancreatic ductal carcinoma, gastric cancer, and HCC. Also, the background tumor types differed between the two cohorts. The frequency of MTAP loss in most tumor types is generally consistent. Next, we analyze the overall survival according to MTAP status, incorporating the national follow-up data since we presented at ESMO 2024. MTAP loss group continued to demonstrate significant prognosis with median overall survival of 14.8 months compared to 37.4 months for the wild-type group with a hazard ratio of 2.53. When analyzed by cancer type, MTAP loss showed particularly poor prognosis in urothelial carcinoma and biliary tract cancer. Furthermore, we re-evaluated the prognosis of overall survival in patients treated with immune checkpoint inhibitors. MTAP loss tumor continued to demonstrate a significantly shorter progression-free survival, with a median progression-free survival of 3.4 months compared to 5.8 months for the wild-type group, with a hazard ratio of 1.74. This trend of shorter progression-free survival was particularly notable in melanoma. And furthermore, to explore the mechanism of immune resistance, we performed deconvolution and gene-set analysis using the transcript data from MONSTER SCREEN 2 study. The tumor immune microenvironment analysis using X-cell showed that MTAP loss tumor showed a significant reduction in infiltration of CD4-positive T-cells and CD8-positive T-cells and M2 macrophages compared to MTAP wild-type tumor. And using Hallmark, C1, and C2 collections of GSEA gene-set enrichment analysis showed MTAP wild-type tumor showed prominent enrichment of transcriptome programs located on chromosome 9p21 and stronger complement activation and B-cell-related signaling. Importantly, when we focus on the C1 collections, we can observe MTAP wild-type tumor shows prominent enrichment of type 1 interferon response genes on chromosome 9p21, whereas MTAP loss tumor shows significantly negative enrichment for these 9p21-encoded type 1 interferon response genes. In conclusion, MTAP loss defines a clinically adverse subset characterized by inferior overall survival and shorter progression-free survival with immune checkpoint inhibitors. Transcriptomic analysis revealed MTAP loss tumor showed significantly reduced infiltration of CD4-positive T-cells and CD8-positive T-cells, and significantly negative enrichment for type I interferon response genes and B-cell-related signaling. These findings provide a mechanistic context for observed clinical resistance to immune checkpoint inhibitors. These are our key conclusions. Thank you.
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