Gender disparities in clinical outcomes of urothelial carcinoma linked to X chromosome gene KDM6A mutation

Objective KDM6A, a representative tumour suppressor gene with sex bias, is frequently altered in urothelial carcinoma (UC). The specific impacts of KDM6A mutations on gender-based clinical outcomes in UC remain poorly understood.Methods and analysis We enrolled 2438 patients with UC from seven independent real-world cohorts possessing comprehensive clinical and genomic data. Point mutations and homozygous deletions of KDM6A are categorised as KDM6AMut. We assessed the correlation between gender disparities in relation to KDM6A status and clinical outcomes, as well as genomic and immunological profiles.Results KDM6A mutations were identified in 679 of the 2306 patients with UC (29.4%), with 505 of 1768 (28.6%) in men and 174 of 538 (32.3%) in women. KDM6A mutations correlated with enhanced overall survival exclusively in male patients but were linked to improved outcomes following adjuvant chemotherapy only in female patients. Concerning immunotherapeutic responses, KDM6AMut male patients displayed the most favourable clinical outcomes, whereas KDM6AMut female patients demonstrated the least favourable outcomes. Independent of gender variations, KDM6AMut patients exhibited heightened androgen receptor and diminished oestrogen receptor 1 filtered regulon activity. Additionally, KDM6AMut male patients showed increased infiltration of T cells, cytotoxic T cells and NK cells with enriched neoantigens, in contrast to KDM6AMut female patients who manifested a more pronounced angiogenesis signature.Conclusion Our findings offer preliminary clinical evidence accentuating KDM6A alterations as a promising prognostic and predictive biomarker while elucidating the gender disparities observed in patients with UC.