Lethal clinical outcome and chemotherapy and immunotherapy resistance in patients with urothelial carcinoma with MDM2 amplification or overexpression

• DOI: 10.1136/jitc-2024-010964
• Publication Date: 2025-01-07T02:00:29Z
• Authors: Kaifeng Jin; Yawei Ding; Jingtong Xu; Zhaopei Liu; Han Zeng; Xiaohe Su; Lingkai Zhang; Jiaxing Sun; Yuzhen Wu; Hailong Liu; Yuan Chang; Yu Zhu; Zewei Wang; Le Xu; Weijuan Zhang; Jiejie Xu
• Keywords: Immunotherapy Biomarkers; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; RC254-282

The E3 ubiquitin ligase murine double minute 2 (MDM2) binds the p53 transcriptional activation domain and acts as a potent inhibitor of TP53 pathway, one three most crucial oncogenic pathways in urothelial carcinoma (UC). However, clinical significance impact on tumor immune contexture MDM2 amplification UC remain unclear. This study analyzed 240 patients with matched annotations from two local cohorts (ZSHS cohort FUSCC cohort). We assessed correlation between status outcomes, therapeutic efficacy, immunological characteristics by immunohistochemical analysis targeted sequencing. Additionally, 2264 samples five independent external cohorts, genomic, transcriptomic, data, were used for validation. (MDM2 Amp) or protein overexpression (MDM2OE) was associated inferior overall survival cohort, Log-rank p<0.001; p=0.030) reduced response to platinum-based chemotherapy p<0.001) well anti-PD-1/PD-L1 immunotherapy (FUSCC p=0.016) UC, irrespective TP53/p53 status. further linked high-grade tumors dedifferentiated morphology. In addition, an immuno-evasive characterized lower proportion tertiary lymphoid structure infiltration, abundance CD8+ T cells, IFN-γ+ GZMB+ decreased expression checkpoint molecules including programmed death-ligand 1 (PD-L1), death-1 (PD-1) cytotoxic T-lymphocyte-associated 4 (CTLA-4). defines lethal subset prognosis resistance both These are morphology immunosuppressive microenvironment. Accurate assessment can improve risk stratification enable personalized genomics-guided treatment UC.