Gender disparities in clinical outcomes of urothelial carcinoma linked to X chromosome gene KDM6A mutation
Weijuan Zhang,
Jiejie Xu,
Hailong Liu,
Yu Zhu,
Zewei Wang,
Zhaopei Liu,
Yuan Chang,
Yiwei Wang,
Le Xu,
Ge Liu,
Kaifeng Jin,
Bingyu Li,
Ziyue Xu,
Jingtong Xu,
Xiaohe Su
Affiliations
Weijuan Zhang
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Jiejie Xu
NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Hailong Liu
Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yu Zhu
1 School of Nursing, Anhui University of Chinese Medicine, Hefei, Anhui, China
Zewei Wang
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
Zhaopei Liu
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
Yuan Chang
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
Yiwei Wang
Department of Urology, Shanghai Ninth People`s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Le Xu
Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Ge Liu
NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Kaifeng Jin
NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Bingyu Li
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Ziyue Xu
NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Jingtong Xu
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Xiaohe Su
NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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.
