Expression of the epigenetic H3K27me3 modifier genes KDM6A and EZH2 in patients with upper tract urothelial carcinoma.

Abstract

The development of upper tract urothelial carcinoma (UTUC) has been associated with the ingestion of aristolochic acid (AA) in Chinese herbs. The tumors are more malignant and patients have a worse prognosis in China compared with that in Western countries. Recently, whole-genome and exome sequencing of AA-associated UTUCs found that the most frequently mutated gene was lysine demethylase 6A (KDM6A). However, its biological role and clinical significance have not yet been defined in patients with UTUC in China. A total of 108 surgically resected UTUC samples were obtained. Using immunohistochemistry, the protein expression level of KDM6A in the tumors was investigated together with the clinical and pathological characteristics of the patients, including survival times. In the present study, the expression level of KDM6A was significantly lower in UTUC specimens compared with that in samples from the normal urothelium. Lower KDM6A expression was also found to be significantly associated with a higher tumor grade and shorter cancer-specific and disease-free survival times (P=0.023 and P=0.033, respectively). In addition, using immunohistochemical analysis, no positive association was found between KDM6A expression and the expression of H3K27me3 or histone-lysine N-methyltransferase EZH2, a histone methyltransferase that generates H3K27me3. The results of the present study indicated that decreased KDM6A expression level was significantly associated with tumor grade and decreased survival time in UTUC, suggesting that KDM6A expression could be used as a prognostic marker in patients with UTUC in China.