Introduction: KMT2 (lysine methyltransferase) family enzymes exert epigenetic regulation to active gene transcription. KMT2C are mainly involved in enhancer-associated H3K4me1, and is also the top mutated genes in cancer (6.6% in pan-cancer). Currently, the clinical significance of KMT2C mutations in prostate cancer is understudied. Methods: We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cfDNA-based liquid biopsy test results in this study. We explored the association of KMT2C mutations with other mutations and investigates the prognostic significance of KMT2C mutation measured by overall survival (OS) and castration-resistance free survival (CFS). In addition, we explored the prognostic value of KMT2C mutation in different patient subgroups. Results: The KMT2C mutation rate in this cohort is 7.24% (16/221). KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CFS and OS (CFS: mutated: 9.9 vs. WT: 22.0 months, p=0.015; OS: mutated: 71.9 vs. WT 137.4 months, p=0.012). KMT2C mutation was also an independent risk factor in OS [HR: 3.815 (1.461, 9.96), P=0.006] in multivariate analyses. Besides, we also explored the association of KMT2C mutations and other genes, and the results showed that KMT2C mutation was related to Serine/Threonine-Protein Kinase 11 (STK11, p=0.004) and Catenin Beta 1 (CTNNB1, p=0.008) mutations. For OS, KMT2C mutation was significantly associated with survival in patient subgroups with PI3K pathway mutation (HR: 6.64, p=0.009) or WNT pathway mutation (HR: 2.44, p=0.043). Conclusions: KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CFS and OS, and KMT2C mutation was associated with STK11 and CTNNB1 mutations. Furthermore, KMT2C mutation was significantly associated with survival in certain patient subgroups, such as patients with PI3K and WNT pathway mutation, etc. SOURCE OF Funding: The Natural Science Foundation of China (NSFC 81902577); The Research Foundation for the Postdoctoral Program of Sichuan University (2021SCU12014).
