Pd41-02 Impact of Kmt2 Gene Alterations on Survival Outcomes in Upper Tract Urothelial Carcinoma

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma III (PD41)1 May 2024PD41-02 IMPACT OF KMT2 GENE ALTERATIONS ON SURVIVAL OUTCOMES IN UPPER TRACT UROTHELIAL CARCINOMA Muneeb Alam, Andrew B. Katims, Jacob E. Tallman, Wesley Yip, Eugene J. Pietzak, Hikmat Al-Ahmadie, Bernard H. Bochner, Kwanghee Kim, David B. Solit, and Jonathan A. Coleman Muneeb AlamMuneeb Alam , Andrew B. KatimsAndrew B. Katims , Jacob E. TallmanJacob E. Tallman , Wesley YipWesley Yip , Eugene J. PietzakEugene J. Pietzak , Hikmat Al-AhmadieHikmat Al-Ahmadie , Bernard H. BochnerBernard H. Bochner , Kwanghee KimKwanghee Kim , David B. SolitDavid B. Solit , and Jonathan A. ColemanJonathan A. Coleman View All Author Informationhttps://doi.org/10.1097/01.JU.0001008568.76803.f1.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The histone-lysine N-methyltransferase family encompasses proteins that impart epigenetic modifications through lysine methylation of histone H3. These proteins are encoded by the KMT2 family of genes, which are frequently altered in upper tract urothelial carcinoma (UTUC). The purpose of this study is to evaluate the association between KMT2 alterations and outcomes in UTUC. METHODS: Patients diagnosed with UTUC who underwent targeted exome sequencing of up to 505 genes were identified. Patients whose sequencing was performed on a co-occurring bladder tumor were excluded. Tumor mutational burden (TMB) was determined based on the rate of non-synonymous mutations (mut/mB) and compared between groups using the Wilcoxon rank-sum and one-way ANOVA tests. Gene enrichment was evaluated using the false discovery method with q<0.05 considered statistically significant. Survival analysis was performed with the Kaplan-Meier method using the log-rank test to evaluate metastasis-free (MFS) and overall survival (OS) starting at the date of diagnosis. RESULTS: A total of 285 patients were identified for analysis. Median age was 67.5 years (IQR 60.8, 73.7) and 112 (39.3%) patients were female. Median follow-up was 37.9 months (IQR 21.8, 60.5). Definitive surgery was performed in 252 patients, and final pathology demonstrated pT0 (2.4%), pTis (1.6%), pTa (16.3%), pT1 (12.7%), pT2 (11.1%), pT3/4 (35.1%), and pTanyN1-3 (19.8%) disease. Metastatic disease occurred in 52.2% of the cohort. KMT2 alterations included KMT2A (9%), KMT2B (14%), KMT2C (18%), and KMT2D (43%). Median TMB was higher in patients with at least one KMT2 alteration (10.5 vs. 5.9 mut/mB, p<0.001) and was highest for those with alterations in KMT2A (28.1 mut/mB) (Figure 1A). Alterations in KMT2C were associated with superior MFS (HR 0.37, 95% CI 0.25-0.56) and OS (HR 0.51, 95% CI 0.31-0.85). KMT2C-altered tumors were enriched in FGFR3 alterations (60.4% vs. 34.5%, q=0.13), and KMT2C/FGFR3 co-altered tumors demonstrated superior MFS compared to both FGFR3 (HR 0.15, p<0.01) and KMT2C alteration alone (HR 0.17, p<0.01) (Figure 1B). CONCLUSIONS: UTUC demonstrates a high frequency of KMT2 gene alterations, which are associated with increased TMB and metastasis. Further evaluation is warranted to better understand the association between KMT2C and outcomes in UTUC. Download PPT Source of Funding: Ruth L. Kirschstein T32 National Research Service Award © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e886 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Muneeb Alam More articles by this author Andrew B. Katims More articles by this author Jacob E. Tallman More articles by this author Wesley Yip More articles by this author Eugene J. Pietzak More articles by this author Hikmat Al-Ahmadie More articles by this author Bernard H. Bochner More articles by this author Kwanghee Kim More articles by this author David B. Solit More articles by this author Jonathan A. Coleman More articles by this author Expand All Advertisement PDF downloadLoading ...