British journal of cancer · 2026
Lethal clinical outcome and immuno-fibrotic contexture in refractory urothelial carcinoma harboring MYC amplification and overexpression.
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Zhang Lingkai, Liu Zhaopei, Ding Yawei, Sun Jiaxing, Wu Yuzhen, Shi Jinming, Su Xiaohe, Jin Kaifeng, Zeng Han, Chang Yuan, Xu Le, Zhang Weijuan, Wang Zewei, Liu Hailong, Zhu Yu, Xu Jiejie
Аннотация
BACKGROUND: The MYC proto-oncogene is frequently overexpressed (OE) and orchestrates key programs in urothelial carcinoma (UC). However, its impact on clinical outcomes, biological behaviors, and tumor microenvironment (TME) in UC patients remains unclear.
METHODS: This study included 250 UC patients with matched clinical annotations from two in-house cohorts (ZSHS and FUSCC cohorts). The MYC status was determined by immunohistochemical analysis and targeted sequencing. We investigated the associations between MYC status and clinical outcomes, tumor biological behaviors, and TME features. Additionally, 1603 UC patients from three external datasets were used for validations.
RESULTS: MYC OE was detected in 25.2% of UC patients, and was associated with advanced tumor stage, higher histological grade, and the presence of lymphovascular invasion in the ZSHS cohort. Patients with MYC OE or MYC amplification delineated the worst prognosis and exhibited resistance to platinum-based chemotherapy and PD-(L)1 blockade, independent of classical basal/luminal status. Mechanistically, MYC-OE UC displayed a hybrid/partial EMT phenotype characterized by high-grade tumor budding. This unique cellular state co-occurs with TGFB1-related fibrogenesis and immunosuppression.
CONCLUSIONS: MYC OE defines a lethal subtype with aggressive behaviors and therapeutic resistance in UC patients. Our findings highlight the need for tailored therapeutic strategies for this refractory subtype of UC.
METHODS: This study included 250 UC patients with matched clinical annotations from two in-house cohorts (ZSHS and FUSCC cohorts). The MYC status was determined by immunohistochemical analysis and targeted sequencing. We investigated the associations between MYC status and clinical outcomes, tumor biological behaviors, and TME features. Additionally, 1603 UC patients from three external datasets were used for validations.
RESULTS: MYC OE was detected in 25.2% of UC patients, and was associated with advanced tumor stage, higher histological grade, and the presence of lymphovascular invasion in the ZSHS cohort. Patients with MYC OE or MYC amplification delineated the worst prognosis and exhibited resistance to platinum-based chemotherapy and PD-(L)1 blockade, independent of classical basal/luminal status. Mechanistically, MYC-OE UC displayed a hybrid/partial EMT phenotype characterized by high-grade tumor budding. This unique cellular state co-occurs with TGFB1-related fibrogenesis and immunosuppression.
CONCLUSIONS: MYC OE defines a lethal subtype with aggressive behaviors and therapeutic resistance in UC patients. Our findings highlight the need for tailored therapeutic strategies for this refractory subtype of UC.