Yan Luzhe, Liang Haisu, Qi Tiezheng, Deng Dingshan, Liu Jinhui, He Yunbo, Chen Jinbo, Fan Benyi, Yao Yiyan, Wang Kun, Zu Xiongbing, Chen Minfeng, Dai Yuanqing, Hu Jiao
Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
BMC Cancer. 2025 Feb 19;25(1):297. doi: 10.1186/s12885-025-13698-9.
Bladder cancer (BLCA) is notably associated with advanced age, characterized by its high incidence and mortality among the elderly. Despite promising advancements in models that amalgamate molecular subtypes with treatment and prognostic outcomes, the considerable heterogeneity in BLCA poses challenges to their universal applicability. Consequently, there is an urgent need to develop a new molecular subtyping system focusing on a critical clinical feature of BLCA: senescence.
Utilizing unsupervised clustering on the Cancer Genome Atlas Program (TCGA)-BLCA cohort, we crafted a senescence-associated molecular classification and precision quantification system (Senescore). This method underwent systematic validation against established molecular subtypes, treatment strategies, clinical outcomes, the immune tumor microenvironment (TME), relevance to immune checkpoints, and identification of potential therapeutic targets.
External validations were conducted using the Xiangya cohort, IMvigor210 cohort, and meta-cohort, with multiplex immunofluorescence confirming the correlation between Senescore, immune infiltration, and cellular senescence. Notably, patients categorized within higher Senescore group were predisposed to the basal subtype, showcased augmented immune infiltration, harbored elevated driver gene mutations, and exhibited increased senescence-associated secretory phenotype (SASP) factors expression in the transcriptome. Despite poorer prognoses, these patients revealed greater responsiveness to immunotherapy and neoadjuvant chemotherapy.
Our molecular subtyping and Senescore, informed by age-related clinical features, accurately depict age-associated biological traits and its clinical application potential in BLCA. Moreover, this personalized assessment framework is poised to identify senolysis targets unique to BLCA, furthering the integration of aging research into therapeutic strategies.
膀胱癌（BLCA）与高龄显著相关，其特点是在老年人中发病率和死亡率高。尽管在将分子亚型与治疗及预后结果相结合的模型方面取得了有前景的进展，但BLCA中存在的显著异质性对其普遍适用性构成了挑战。因此，迫切需要开发一种新的分子分型系统，该系统聚焦于BLCA的一个关键临床特征：衰老。
我们利用癌症基因组图谱计划（TCGA）-BLCA队列进行无监督聚类，构建了一个衰老相关分子分类和精准定量系统（Senescore）。该方法针对已确立的分子亚型、治疗策略、临床结果、免疫肿瘤微环境（TME）、与免疫检查点的相关性以及潜在治疗靶点的识别进行了系统验证。
使用湘雅队列、IMvigor210队列和meta队列进行了外部验证，多重免疫荧光证实了Senescore、免疫浸润和细胞衰老之间的相关性。值得注意的是，Senescore分组较高的患者易患基底亚型，表现出增强的免疫浸润，携带更高的驱动基因突变，并且在转录组中衰老相关分泌表型（SASP）因子表达增加。尽管预后较差，但这些患者对免疫治疗和新辅助化疗表现出更高的反应性。
我们基于与年龄相关的临床特征的分子分型和Senescore准确描绘了BLCA中与年龄相关的生物学特征及其临床应用潜力。此外，这个个性化评估框架有望识别BLCA特有的衰老细胞溶解靶点，进一步将衰老研究整合到治疗策略中。
