The Gender-Biased Differential Effect of KDM6A Mutation on Immune Therapy in Urothelial Carcinoma: A Public Database...

Background/Objectives: It is said that genes that escape from X chromosome inactivation (XCI) contribute to gender differences. We analyzed the prognostic role of these genes and identified a gender-biased difference in prognosis according to KDM6A mutation in the immune therapy cohort (IMvigor 210). We also investigate the gender-biased differential effect of KDM6A mutation in several public databases of urothelial carcinoma (UC). Methods: We used AACR GENIE, The Cancer Genome Atlas, International Cancer Genome Consortium, several public databases related to immune therapy, chemotherapy, and BCG treatment. We studied the gender-biased prognostic role of KDM6A mutation in several cohorts and the association between KDM6A mutation and immune-related fractions according to gender. Results: The expression of KDM6A was higher in females than in males in several cohorts. Mutation of KDM6A was observed in about 20-25% of the patients. The rate of KDM6A mutation was higher in females than in males in several cohorts. Kaplan-Meier analysis revealed a gender-biased difference in prognosis between patients with KDM6A mutations and those with the wild-type KDM6A in several cohorts, including the immune therapy cohort. The rate of immune-inflamed type was higher in males than in females in the patients with KDM6A mutation in the IMvigor 210 and UC-GENOME studies. Single-sample Gene Set Enrichment Analysis showed that CD8+ cells and type 1 IFN response fractions and APC co-inhibition fraction were higher in the male than female patients with KDM6A mutation. Similar findings were observed in other immune-related studies (UC-GENOME). Conclusions: The effect of KDM6A mutation on immune therapy varied according to gender, and the status of KDM6A mutation may be a promising biomarker in immune therapy in UC.