Gender disparities in clinical outcomes of urothelial carcinoma linked to X chromosome geneKDM6Amutation

Abstract

ObjectiveKDM6A, a representative tumour suppressor gene with sex bias, is frequently altered in urothelial carcinoma (UC). The specific impacts ofKDM6Amutations on gender-based clinical outcomes in UC remain poorly understood.Methods and analysisWe enrolled 2438 patients with UC from seven independent real-world cohorts possessing comprehensive clinical and genomic data. Point mutations and homozygous deletions ofKDM6Aare categorised asKDM6AMut. We assessed the correlation between gender disparities in relation toKDM6Astatus and clinical outcomes, as well as genomic and immunological profiles.ResultsKDM6Amutations 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.KDM6Amutations 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,KDM6AMutmale patients displayed the most favourable clinical outcomes, whereasKDM6AMutfemale patients demonstrated the least favourable outcomes. Independent of gender variations,KDM6AMutpatients exhibited heightened androgen receptor and diminished oestrogen receptor 1 filtered regulon activity. Additionally,KDM6AMutmale patients showed increased infiltration of T cells, cytotoxic T cells and NK cells with enriched neoantigens, in contrast toKDM6AMutfemale patients who manifested a more pronounced angiogenesis signature.ConclusionOur findings offer preliminary clinical evidence accentuatingKDM6Aalterations as a promising prognostic and predictive biomarker while elucidating the gender disparities observed in patients with UC.