Wang Yizhou, Bhandary Priyanka, Griffin Kevin, Moore Jason H, Li Xue, Wang Zhiping Paul
Department of Computational Biomedicine, Cedars Sinai Medical Center, Los Angeles, CA, United States.
Department of Medicine and Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, United States.
Front Bioinform. 2025 May 19;5:1575790. doi: 10.3389/fbinf.2025.1575790. eCollection 2025.
Bladder cancer shows distinct sex-related patterns, with male patients experiencing significantly higher incidence and female patients facing poorer survival outcomes. This study aimed to investigate the biological mechanisms underlying these differences using integrative multi-omics analysis.
We analyzed bladder cancer data from TCGA and GTEx, including genomic mutations, gene expression profiles, and clinical information. We performed protein-protein interaction analysis, pathway enrichment, survival analysis, and immune cell correlation.
We identified androgen receptor (AR)-related pathways as uniquely enriched in male-specific hub genes, while the Wnt signaling pathway was enriched in female-specific hub genes. In total, 14 male-specific hub genes showed significant sex-biased survival associations, including known markers-DLGAP5, SOX2, LAMA2, and COL5A2-and novel ones such as ERCC5, NID1, ANK2, and others. For females, three hub genes-RAD51C, COL22A1, and COL5A2-were identified as female-specific with survival associations. Additionally, four male-specific hub genes-DAXX, IKBKB, PDGFRA, and PPARG-were immune-related and showed sex-differential correlations with immune cell infiltration, with three of them associated with AR signaling regulation.
These findings provide new insights into the molecular basis of sex differences in bladder cancer and could pave the way for more personalized and effective therapeutic strategies tailored to male and female patients.
膀胱癌呈现出明显的性别相关模式，男性患者的发病率显著更高，而女性患者的生存结果较差。本研究旨在通过综合多组学分析探究这些差异背后的生物学机制。
我们分析了来自TCGA和GTEx的膀胱癌数据，包括基因组突变、基因表达谱和临床信息。我们进行了蛋白质-蛋白质相互作用分析、通路富集分析、生存分析和免疫细胞相关性分析。
我们发现雄激素受体（AR）相关通路在男性特异性枢纽基因中独特富集，而Wnt信号通路在女性特异性枢纽基因中富集。总共14个男性特异性枢纽基因显示出显著的性别偏向生存关联，包括已知标志物——DLGAP5、SOX2、LAMA2和COL5A2——以及新发现的基因，如ERCC5、NID1、ANK2等。对于女性，三个枢纽基因——RAD51C、COL22A1和COL5A2——被确定为具有生存关联的女性特异性基因。此外，四个男性特异性枢纽基因——DAXX、IKBKB、PDGFRA和PPARG——与免疫相关，并显示出与免疫细胞浸润的性别差异相关性，其中三个与AR信号调节相关。
这些发现为膀胱癌性别差异的分子基础提供了新见解，并可能为针对男性和女性患者的更个性化、更有效的治疗策略铺平道路。
