Sex-Associated Molecular Signature in Bladder Cancer: An Exploratory Multi-Cohort Analysis

Abstract

Introduction: Bladder cancer (BCa) exhibits marked differences between females and males in incidence, presentation, and clinical outcomes. However, the regulatory molecular networks underlying these sex-specific differences remain incompletely understood.

Methods: Publicly available transcriptomic datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were analyzed to identify sex-biased gene expression patterns associated with BCa progression. Sex-annotated GEO datasets were analyzed using cohort-specific and integrated differential expression models. Tumour-by-sex interaction analysis was performed using available tumour and non-tumour bladder specimens. Analyses were complemented by female-versus-male comparisons performed within non-muscle invasive BCa (NMIBC) and muscle invasive BCa (MIBC), exploratory survival analysis in TCGA-BLCA, cross-cancer expression contextualization and exploratory associations with model-predicted drug sensitivity.

Results: XIST emerged as a consistent female-associated marker across BCa subtypes, while RPS4Y1, EIF1AY, KDM5D, and NLGN4Y constituted the most reproducible Y-linked transcripts across male tumors. Female MIBC was further characterized by the upregulation of KRT5, S100A8, CALML3, PI3, and CEACAM6, pointing to stage-specific differences spanning epithelial differentiation, immune signaling and cell adhesion.

Conclusion: Our study reveals distinct sex-specific transcriptional programs in BCa, involving XIST-related and Y chromosome-linked gene activity, with potential implications for disease stage and therapeutic response.