Bladder cancer is approximately 4 times more common in men than in women; however, women tend to present with more aggressive, high-grade tumors, and experience poorer clinical outcomes [1,2]. This sex-based disparity is also evident in the 5-year survival rates, with men having a higher survival rate of 75.1% (95% CI 74.0–76.2) compared to 71.7% (95% CI 70.1–73.4) in women [3]. The disease usually presents at a median age of 55, with a 5-year mortality rate of 23% for localized cancer, rising sharply to 95% for metastatic disease [4]. Delayed diagnostic workup for women with hematuria has been proposed as a contributing factor to poorer outcomes [5]. However, the potential role of biological differences, such as sex-based endocrine influences or other factors, in driving this disparity remains unclear [2,6]. Given the survival difference between men and women, identifying factors linked to adverse outcomes is essential for improving gender-specific management.

Despite notable differences in sex-based incidence and outcomes, bladder cancer management remains largely uniform across genders [2]. This highlights the need to investigate the mechanisms driving these sex-based disparities, which could guide the development of more targeted therapeutic approaches. . Previous research largely focused on the etiology of bladder cancer by highlighting gene alterations such as mutations in TP53, RAS, FGFR3, PIK3CA, KDM6A, and TERT, without adequately addressing sex-based differences. Variations in incidence and outcomes have often been attributed to lifestyle factors such as alcohol and tobacco use rather than exploring potential biological or molecular sex-specific mechanisms [1,7]. However, recent studies have begun to explore other mechanisms, including hormone-related factors, such as androgen receptor (AR) and estrogen receptor beta (ERβ), as well as X chromosome imbalance [1,6].

Advances in Next Generation Sequencing (NGS) have provided valuable insights into the roles of epigenetics, single nucleotide polymorphisms, transcriptional regulation, metabolism, immunity, and X chromosome inactivation in bladder cancer [1,6]. While sex chromosomes, hormones, metabolic, and environmental factors all contribute to these observed differences, research suggests these interactions are complex and warrant further investigation [1,2]. Recent studies in melanoma have highlighted the role of somatic mutations in the sex-based heterogeneity observed in certain cancers, showing that the frequency of somatic mutations can differ between sexes and influence overall survival outcomes [6,8]. In melanoma, men exhibited almost 2-fold higher frequency of somatic missense mutations than women in patients positive for BRAF and NRAS mutations [8]. These findings from melanoma suggest that somatic mutation patterns may underlie sex-based differences in cancer outcomes, providing the rationale for investigating whether similar mechanisms contribute to the disparities observed in bladder cancer.

This study investigates sex-based differences in somatic gene alterations (GAs) and their impact on overall survival in patients with urothelial bladder cancer. We also explored how these GAs influence treatment response; particularly to immune checkpoint inhibitors (ICIs). Our analysis reveals that RB1, CDKN1A, and ERCC2 GAs are significantly more common in male patients, whereas AR GAs are more frequent in females. Among these genes, RB1 exhibits the most pronounced adverse effect on 10-year overall survival. Additionally, all the analyzed GAs were associated with changes in immune cell infiltration patterns; however, no significant differences in ICI’s response were observed. AR GAs, which occur more frequently in women, were strongly associated with decreased monocyte infiltration but showed no significant correlation with CD8⁺ or CD4⁺ T cell infiltration. All GAs had synthetic lethal partners across various cancer subtypes and in bladder cancer, except for ERCC2, which lacked a partner in bladder cancer, and AR, which had no synthetic lethal partner in any cancer subtype.