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urothelial carcinoma (UC). However, the clinical significance and impact on tumor immune contexture of <jats:italic>MDM2<\/jats:italic> amplification in UC remain unclear.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>This study analyzed 240 patients with UC with matched clinical annotations from two local cohorts (ZSHS cohort and FUSCC cohort). We assessed the correlation between <jats:italic>MDM2<\/jats:italic> status and clinical outcomes, therapeutic efficacy, and immunological characteristics by immunohistochemical analysis and targeted sequencing. Additionally, 2264 UC samples from five independent external cohorts, with genomic, transcriptomic, and clinical data, were used for validation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                     <jats:italic>MDM2<\/jats:italic> amplification (<jats:italic>MDM2<\/jats:italic>\n                     <jats:sup>Amp<\/jats:sup>) or protein overexpression (MDM2<jats:sup>OE<\/jats:sup>) was associated with inferior overall survival (ZSHS cohort, Log-rank p&lt;0.001; FUSCC cohort, Log-rank p=0.030) and reduced response to platinum-based chemotherapy (ZSHS cohort, Log-rank p&lt;0.001) as well as anti-PD-1\/PD-L1 immunotherapy (FUSCC cohort, Log-rank p=0.016) in patients with UC, irrespective of <jats:italic>TP53<\/jats:italic>\/p53 status. <jats:italic>MDM2<\/jats:italic> amplification or overexpression was further linked to high-grade UC tumors with dedifferentiated morphology. In addition, UC with <jats:italic>MDM2<\/jats:italic> amplification or overexpression was associated with an immuno-evasive contexture characterized by lower proportion of tertiary lymphoid structure infiltration, lower abundance of CD8<jats:sup>+<\/jats:sup> T cells, IFN-\u03b3<jats:sup>+<\/jats:sup> cells, GZMB<jats:sup>+<\/jats:sup> cells, and decreased expression of immune checkpoint molecules including programmed death-ligand 1 (PD-L1), programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                     <jats:italic>MDM2<\/jats:italic> amplification or overexpression defines a lethal subset of patients with UC with inferior prognosis and resistance to both platinum-based chemotherapy and immunotherapy irrespective of <jats:italic>TP53<\/jats:italic>\/p53 status. These tumors are characterized by dedifferentiated morphology and an immunosuppressive microenvironment. Accurate assessment of <jats:italic>MDM2<\/jats:italic> status can improve risk stratification and enable personalized genomics-guided treatment for patients with UC.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-010964","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T21:00:29Z","timestamp":1736197229000},"page":"e010964","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Lethal clinical outcome and chemotherapy and immunotherapy resistance in patients with urothelial carcinoma with MDM2 amplification or 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