KDM6A expression loss is frequent in low grade non-invasive urothelial carcinomas of the urinary bladder.

Objective: The gene lysine demethylase 6A () located on chromosome Xp11 often shows truncating mutations in urothelial carcinoma. Mutations resulting in protein expression loss can be detected by immunohistochemistry (IHC).

Methods: A tissue microarray with >2,500 bladder tumors was analyzed by IHC. 78 cancers were sequenced for KDM6A.

Results: KDM6A expression loss decreased from 36% of 345 pTaG2 low-grade to 23% of 152 pTaG2 high-grade and 18.5% of 92 pTaG3 tumors (p=0.0004) but not further in pT2-4 cancers (17.2-21.9%). KDM6A staining was unrelated to pT, pN, grade, and overall survival (p>0.1894) in 636 patients with pT2-4 cancers. KDM6A loss was more common in male (22.2%) than in female patients (15.4%; p=0.0067), and in tumors from males with Y-chromosome loss (36.1%) than without Y-loss (16.3%; p<0.0001). A KDM6A loss occurred in all 15 male and in 17 (74%) of 23 female patients with a truncating KDM6A mutation, but only 15 (75%) of 20 male and 17 (81%) of 21 female patients with KDM6A expression loss had a truncating mutation.

Conclusions: KDM6A expression loss is frequent in urothelial carcinoma and mostly due to truncating mutations. KDM6A IHC may be a useful tool for the distinction of neoplastic from non-neoplastic urothelial cells in follow-up examinations of patients with KDM6A deficient cancers.