GNRH family genes contributed to gender-specific disparity of bladder cancer prognosis through exerting opposite regulatory roles between males and females

Abstract

Purpose: There is gender-specific disparity in bladder cancer (BlCa) prognosis. Female BlCa patients present with more advanced tumor and have higher risks of disease recurrence, progression, and mortality than males. Since gonadotropin-releasing hormone (GNRH) family genes were critical genes in gender-related biological activity and could be detected in BlCa specimens, this study aimed to explore potential roles of GNRH1 and GNRHR in gender disparity of BlCa.

Methods: RNA-sequencing data from The Cancer Genome Atlas Bladder Urothelial Carcinoma dataset, IMvigor210 immunotherapy cohort and Cancer Cell Line Encyclopedia database were used to compare potential roles of GNRH1 and GNRHR in males and females, respectively. Gene set enrichment analysis was used to analyze the biological functions.

Results: Males with higher GNRH1 and GNRHR have better overall survival (P < 0.05, HR < 1), while females with higher expression have a trend toward worse overall survival (P < 0.05, HR > 1). Gene set enrichment analysis identified GNRH1 and GNRHR exert opposite regulatory roles in myogenesis (M5909), interferon-α response (M5911), interferon-γ response (M5913), inflammatory response (M5932) and TNF-α signaling via NF-κβ (M5890) between males and females. The five functions are up-regulated in females (NES > 0), while down-regulated in males (NES < 0). GNRH1 in females was positively correlated with CD3D (R-value > 0 and P < 0.05), while GNRHR in males was negatively correlated with CD247, CD3D and CD3E (R-value < 0 and P < 0.05).

Conclusion: GNRH1 and GNRHR have opposite effects on overall survival in different genders, and exert opposite roles in immune-related functions between different genders, which could emerge as a contributor to gender disparity of BlCa prognosis.

Keywords: Bladder cancer; GNRH; Gender; Immunotherapy; Prognosis.