The gene coding for
histone methyltransferase KMT2D is found among the top mutated genes in upper tract urothelial
carcinoma (UTUC); however, there is a lack of data regarding its association with clinicopathologic features as well as survival outcomes. Therefore, we aimed to investigate KMT2D expression, mutation patterns, and their utility as prognostic
biomarkers in patients with UTUC. A single-center study was conducted on
tumor specimens from 51 patients treated with radical
nephroureterectomy (RNU). Analysis of KMT2D
protein expression was performed using immunohistochemistry (IHC). Customized next-generation sequencing (NGS) was used to assess alterations in KMT2D exons. Cox regression was used to assess the relationship of KMT2D
protein expression and mutational status with survival outcomes. KMT2D expression was increased in patients with a previous history of
bladder cancer (25% vs. 0%, p = 0.02). The NGS analysis of KMT2D exons in 27 UTUC
tumors revealed a significant association between pathogenic KMT2D variants and
tumor location (p = 0.02). Pathogenic KMT2D variants were predominantly found in patients with non-pelvic or multifocal
tumors (60% vs. 14%), while the majority of patients with a pelvic
tumor location (81% vs. 20%) did not harbor pathogenic KMT2D alterations. Both IHC and NGS analyses of KMT2D failed to detect a statistically significant association between KMT2D
protein or KMT2D gene alteration status and clinical variables such as stage/grade of the disease or survival outcomes (all p > 0.05). KMT2D alterations and
protein expression were associated with UTUC features such as multifocality, ureteral location, and previous
bladder cancer. While KMT2D
protein expression and KMT2D mutational status do not seem to have prognostic value in UTUC, they appear to add information to improve clinical decision-making regarding the type of
therapy.