# Sex-related differences in gene expression in early-stage bladder cancer revealed by whole-transcriptome sequencing

## TL;DR

This study finds sex-related gene expression differences in early-stage bladder cancer, with distinct patterns between men and women.

## Contribution

The study reveals unique and shared gene expression profiles in male and female bladder cancer patients using whole-transcriptome sequencing.

## Key findings

- Female-specific genes were enriched in immune-related pathways, while male-specific genes were linked to cell cycle and androgen signaling.
- A significant number of differentially expressed genes were unique to each sex, with only a small overlap between them.
- S100A14 was the only gene with a confirmed sex-dependent expression pattern, suggesting potential for sex-specific treatment approaches.

## Abstract

Bladder cancer (BC) is significantly more prevalent in men than in women, yet female patients often experience higher recurrence rates and poorer prognosis.

Our study aimed to investigate sex-specific gene expression differences in early-stage BC using whole-transcriptome sequencing. A total of 51 patients diagnosed with low-grade Ta stage non-muscle-invasive bladder cancer were recruited. Paired tissue samples from tumor lesions and adjacent healthy bladder mucosa (BM) were analyzed to identify differentially expressed genes (DEGs).

Among the top 100 most significant DEGs for each gender, overwhelmingly more upregulated in BC comparing with BM were in male than female tissues (90% vs. 19%). The most significantly altered expression in female BC tissues included MT-ND6, ARL4C, ASGR1, MYBL1, and SCAMP5, whereas in males, ONECUT2, SPEG, CTSE, GJB2, and SYNM. Notably, 753 DEGs were unique to female patients, while 3989 were specific to males, with 1633 shared between both sexes. Functional annotation revealed that female-unique DEGs were significantly enriched in immune-related pathways, including regulation of leukocyte activation and cell–cell adhesion, and lymphocyte differentiation. Whereas male-unique DEGs were predominantly associated with pathways related to cell cycle regulation, mitochondrial function, and androgen receptor signaling. Immune-related gene expression indicated that female-specific DEGs were involved in leukocyte activation and antigen receptor signaling, whereas male-specific DEGs were linked to B-cell activation and neutrophil-mediated immune responses. A two-factor interaction model identified S100A14 as the only protein-coding gene whose expression exhibited a significant sex-dependent pattern, with four additional genes (GJB2, DSC2, TM4SF and ALOX15B) showing a probable interaction effect.

These findings provide preliminary evidence supporting further investigation of sex-specific approaches to BC management.

The online version contains supplementary material available at 10.1186/s12885-026-15666-3.