MP40-16: Expression Analysis and Mutational Status of Histone Methyltransferase KMT2D in Upper Tract Urothelial Carcinoma

Ekaterina Laukhtina*, Ursula Lemberger, Andreas Bruchbacher, Dafina Ilijazi, David D’Andrea, Martin Susani, Vienna, Austria, Dmitry Enikeev, Moscow, Russian Federation, Eva Compérat, Shahrokh F. Shariat, Melanie R. Hassler, Vienna, Austria

Introduction: 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 and mutation patterns and their utility as prognostic biomarkers in patients with UTUC.

Methods: A retrospective single-center study was conducted on tumor specimens from 51 patients treated with radical nephroureterectomy (RNU). Analysis of KMT2D expression on the protein level was performed by immunohistochemistry (IHC). Customized Next Generation Sequencing (NGS) was used to assess alterations in KMT2D exons. Cox-regression analyses were used to correlate KMT2D protein expression and mutational status with survival outcomes such as disease-free and overall survival.

Results: KMT2D expression was increased in patients with a previous history of bladder cancer (25% vs. 0%, p=0.02). 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 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 as well as survival outcomes (all p>0.05).

Conclusions: In this study, KMT2D protein expression and KMT2D mutational status did not emerge as prognostic markers for UTUC. However, KMT2D alterations and protein expression were associated with features of biologically aggressive UTUC such as multifocality, ureteral location, and previous bladder cancer. Therefore, KMT2D seems to hold the potential of improving our clinical decision in UTUC regarding perioperative systemic therapy and/or additional intravesical therapy.

Source of Funding: None.