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中国癌症防治杂志

中国癌症防治杂志 ›› 2025, Vol. 17 ›› Issue (6): 705-714.doi: 10.3969/j.issn.1674-5671.2025.06.08

• 论著 • 上一篇    下一篇

多组学分析揭示Y染色体丢失在膀胱癌中的作用及临床意义

  

  1. 广西医科大学第一附属医院泌尿外科；广西医科大学基因组与个体化医学研究中心； 广西医科大学第一附属医院代谢与健康广西院士工作站；广西医科大学附属肿瘤医院内科
  • 出版日期:2025-12-25 发布日期:2026-02-02
  • 通讯作者: 李天宇 E-mail：litianyu@gxmu.edu.cn
  • 基金资助:
    国家自然科学基金项目（82560483）；广西自然科学基金项目（2025GXNSFAA069715）；广西重点研发计划项目（桂科AB25069011）；广西研究生教育创新计划项目（YCSW2025288）

Multi⁃omics analysis reveals the role and clinical significance of the loss of Y chromosome in bladder cancer

  • Online:2025-12-25 Published:2026-02-02

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摘要： 目的 探究Y染色体丢失（loss of Y chromosome, LOY）在膀胱癌中的作用及临床意义。方法 收集2018年1月至2019年10月在广西医科大学第一附属医院接受全膀胱切除术的44例男性膀胱癌组织样本及临床资料。基于Y染色体转录特征（Y chromosome transcriptional signature，YchrS），采用单样本基因集富集分析（single⁃sample gene set enrichment analysis，ssGSEA）对患者的全转录组测序数据进行评分，将患者分成高YchrS评分组和低YchrS评分组。采用Kaplan⁃Meier法评估两组患者预后，并通过差异表达分析及基因集富集分析（gene set enrichment analysis，GSEA）揭示其潜在的分子特征。利用质谱流式细胞术（cytometry by time of flight,CyTOF）分析两组肿瘤中免疫细胞的多样性。基于公共数据库的单细胞转录组测序数据（HRA000212），通过细胞分化轨迹及细胞通讯分析LOY上皮细胞的特征。使用CMap数据库识别潜在有效治疗药物。 结果 低YchrS评分组膀胱癌患者表现出更短的总生存期（P=0.006）及更高的肿瘤分级（P=0.036）。该组上调基因富集于细胞周期调控、DNA复制及染色体分离等相关生物过程（P<0.05），并表现出p53抑制基因的评分升高和p53诱导基因的评分降低（均P<0.001）。相较于其他上皮细胞，LOY上皮细胞的免疫相关信号通路激活，且与髓系细胞和T细胞存在较强的相互作用。CyTOF分析显示，低YchrS评分组表现为调节性T（regulatory T，Treg）细胞富集，CD4+ T细胞的CD279（PD⁃1）表达上调。CMap数据库分析结果显示，周期蛋白依赖性激酶（cyclin⁃dependent kinase，CDK）抑制剂（如哌柏西利）和组蛋白脱乙酰酶（histone deacetylase，HDAC）抑制剂是低YchrS评分组膀胱癌患者的潜在治疗药物。结论 LOY与膀胱癌患者不良预后密切相关，其促癌机制可能与p53抑制及免疫抑制有关。CDK抑制剂和HDAC抑制剂是LOY膀胱癌患者潜在的治疗药物。

关键词: 膀胱癌, Y染色体丢失, 肿瘤微环境, 调节性T细胞

Abstract: Objective To investigate the role and clinical significance of the loss of  Y chromosome (LOY) in bladder cancer. Methods  Tissue samples and clinical data were collected from 44 male patients with bladder cancer undergoing radical cystectomy at the First Affiliated Hospital of Guangxi Medical University between January 2018 and October 2019. Whole⁃transcriptome sequencing data were analyzed and scored based on Y chromosome transcriptional signature (YchrS） using single⁃sample gene set enrichment analysis (ssGSEA). Patients were stratified into high and low YchrS score groups. The prognosis of the two groups were evaluated using the Kaplan⁃Meier method, and the potential molecular characteristics were revealed via differential expression analysis and gene set enrichment analysis （GSEA）. The diversity of immune cells in the two groups was analyzed using cytometry by time of flight (CyTOF). Single⁃cell transcriptomic sequencing data from a public database (HRA000212) was used to characterize LOY epithelial cells through cell differentiation trajectories and cell communication analysis. The CMap  database was utilized to identify potential therapeutic agents. Results  Patients with bladder cancer in the low YchrS score group exhibited shorter overall survival (P=0.006) and higher tumor grade (P=0.036). Upregulated genes in low YchrS score group were enriched in biological processes related to the cell cycle regulation, DNA replication, and chromosome segregation (P<0.05), showing elevated scores for p53⁃repressed genes and reduced scores for p53⁃induced genes (all P<0.001). Compared with other epithelial cells, LOY epithelial cells displayed activation of immune⁃related signaling pathways and stronger interactions with myeloid cells and T cells. CyTOF analysis revealed an enrichment of regulatory T (Treg) cells and upregulated expression of CD279 (PD⁃1) on CD4+ T cells in the low YchrS score group. CMap analysis indicated that cyclin⁃dependent kinase (CDK) inhibitors (e.g., Palbociclib) and histone deacetylase (HDAC) inhibitors were potential therapeutic agents for bladder cancer patients in the low YchrS score group. Conclusions LOY is strongly associated with poor prognosis in bladder cancer patients, with its tumorigenic mechanism may involve p53 suppression and immune suppression. CDK inhibitors and HDAC inhibitors serve as potential therapeutic agents for the LOY bladder cancer patients.

Key words: Bladder cancer, Loss of Y chromosome, Tumor microenvironment, Regulatory T cells 

中图分类号: 

  • R737.14