Mutations in epigenetic regulator KMT2C detected by liquid biopsy are associated with worse survival in prostate cancer patients
SHA ZHU#, NANWEI XU#, JIAYU LIANG, FENGNIAN ZHAO, ZILIN WANG, YUCHAO NI, JINDONG DAI, JINGE ZHAO, XINGMING ZHANG, JUNRU CHEN, GUANGXI SUN, PENGFEI SHEN*, HAO ZENG*
Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
* Corresponding Authors: PENGFEI SHEN. Email: ; HAO ZENG. Email:
Oncology Research 2023, 31(4), 605-614. https://doi.org/10.32604/or.2023.028321
Received 12 December 2022; Accepted 17 April 2023; Issue published 25 June 2023
Abstract
Background: KMT2 (lysine methyltransferase) family enzymes are epigenetic regulators that activate gene transcription.
KMT2C is mainly involved in enhancer-associated H3K4me1, and is also one of 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 cell-free DNA-based liquid biopsy test results in this study. We investigated the association between
KMT2C mutations, other mutations, and pathways. Furthermore, we evaluated the prognostic value of
KMT2C mutations, measured by overall survival (OS) and castration resistance-free survival (CRFS). Also, we explored the prognostic value of
KMT2C mutations in different patient subgroups. Lastly, we investigated the predictive value of
KMT2C mutations in individuals receiving conventional combined anti-androgen blockade (CAB) and abiraterone (ABI) as measured by PSA progression-free survival (PSA-PFS).
Results: The
KMT2C mutation rate in this cohort is 7.24% (16/221).
KMT2C-mutated patients showed worse survival than
KMT2C-wild type (WT) patients regarding both CRFS and OS (CRFS: mutated: 9.9
vs. WT: 22.0 months,
p = 0.015; OS: mutated: 71.9
vs. WT 137.4 months,
p = 0.012).
KMT2C mutations were also an independent risk factor in OS [hazard ratio: 3.815 (1.461, 9.96),
p = 0.006] in multivariate analyses. Additionally, we explored the association of
KMT2C mutations with other genes. This showed that
KMT2C mutations were associated with Serine/Threonine-Protein Kinase 11 (
STK11,
p = 0.004) and Catenin Beta 1 (
CTNNB1,
p = 0.008) mutations. In the CAB treatment,
KMT2C-mutated patients had a significantly shorter PSA-PFS compared to
KMT2C-WT patients. (PSA-PFS: mutated: 9.9
vs. WT: 17.6 months,
p = 0.014). Moreover,
KMT2C mutations could effectively predict shorter PSA-PFS in 10 out of 23 subgroups and exhibited a strong trend in the remaining subgroups.
Conclusions: KMT2C-mutated patients showed worse survival compared to
KMT2C-WT patients in terms of both CRFS and OS, and
KMT2C mutations were associated with
STK11 and
CTNNB1 mutations. Furthermore,
KMT2C mutations indicated rapid progression during CAB therapy and could serve as a potential biomarker to predict therapeutic response in prostate cancer.
Keywords
Supplementary Material
Supplementary Material File
Cite This Article
ZHU, S., XU, N., LIANG, J., ZHAO, F., WANG, Z. et al. (2023). Mutations in epigenetic regulator
KMT2C detected by liquid biopsy are associated with worse survival in prostate cancer patients.
Oncology Research, 31(4), 605–614. https://doi.org/10.32604/or.2023.028321