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 ca...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.展开更多
目的探究赖氨酸特异性甲基转移酶2C(lysine specific methyltransferase 2C,KMT2C)在胃癌发生发展中的作用及机制。方法通过TCGA数据库分析KMT2C在胃癌与癌旁的表达差异。采用Western blot检测KMT2C在胃癌与癌旁临床样本中的表达差异。...目的探究赖氨酸特异性甲基转移酶2C(lysine specific methyltransferase 2C,KMT2C)在胃癌发生发展中的作用及机制。方法通过TCGA数据库分析KMT2C在胃癌与癌旁的表达差异。采用Western blot检测KMT2C在胃癌与癌旁临床样本中的表达差异。通过Kaplan-Meier Plotter数据库分析KMT2C对胃癌患者预后的影响。采用细胞实验(克隆形成、EdU及CCK-8检测)及皮下瘤负荷模型检测KMT2C在体内外对胃癌细胞增殖能力的影响。结果KMT2C在胃癌中高表达。胃癌患者中KMT2C高表达组相对于KMT2C低表达组预后较差。敲减KMT2C在体内外均有抑制胃癌细胞增殖的作用。基因集富集分析(GSEA)发现KMT2C影响c-Myc信号通路。敲减KMT2C后,H3K4me1蛋白表达水平降低,同时,CDK4的mRNA与蛋白表达水平降低。KMT2C与c-Myc核内结合促进了c-Myc与CDK4的启动子区域的结合。结论KMT2C通过影响c-Myc/CDK4信号通路促进胃癌细胞增殖。展开更多
基金This work was supported by the Natural Science Foundation of China(NSFC 81902577)the Research Foundation for the Postdoctoral Program of Sichuan University(2021SCU12014).
文摘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.
