Distribution of Molecular Subtypes in Muscle-invasive Bladder Cancer Is Driven by Sex-specific Differences

Muscle-invasivebladder cancer (MIBC)is a sex-biasedcancer withahigher incidence in men but worse outcomes inwomen. The root cause behind these observations remains unclear.Toinvestigatewhether sex-specific tumorbiologycouldexplainthedifferences in clinical behavior of MIBC, we analyzed the transcriptome profiles from transurethral resected bladder tumors of 1000 patients. Female tumors expressed higher levels of basal- and immune-associated genes, while male tumors expressed higher levels of luminal markers. Using molecular subtyping, we found that the rates of the basal/ squamous subtype were higher in females than in males. Males were enriched with tumors of the luminal papillary (LumP) and neuroendocrine-like subtypes. Male MIBC tumors had higher androgen response activity across all luminal subtypes and male patients with LumP tumors were younger. Taken together, these data confirm differences inmolecular subtypesbasedonsex.The roleoftheandrogenresponsepathwayin explaining subtype differences between men and women should be studied further. Patient summary: We explored the sex-specific biology of bladder cancer in 1000 patients and found that women had more aggressive cancer with higher immune activity. Men tended toward less aggressive tumors that showed male hormone signaling, suggesting that male hormones may influence the type of bladder cancer that a patient develops.

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