摘要Background:DNA methylation is involved in numerous biologic events and associates with transcriptional gene silencing,playing an important role in the pathogenesis of endometrial cancer.ESR1/PGR frequently undergoes de novo methylation and loss expression in a wide variety of tumors,including breast,colon,lung,and brain tumors.However,the mechanisms underlying estrogen and progesterone receptors (ER/PR) loss in endometrial cancer have not been studied extensively.The aims of this study were to determine the expression of DNA (cytosine-5)-methyltransferase 3A/3B (DNMT3A/3B) in endometrial cancer to investigate whether the methylation catalyzed by DNMT3A/3B contributes to low ER/PR expression.Methods:The clinicopathologic information and RNA-Seq expression data of DNMT3A/3B of 544 endometrial cancers were derived from The Cancer Genome Atlas (TCGA) uterine cancer cohort in May 2018.RNA-Seq level of DNMT3A/3B was compared between these clinicopathologic factors with t-test or one-way analysis of variance.Results:DNMT3A/3B was overexpressed in endometrioid carcinoma (EEC) and was even higher in non-endometrioid carcinoma (NEEC) (DNMT3A,EEC vs.NEEC:37.6％ vs.69.9％,t=-7.440,P ＜ 0.001;DNMT3B,EEC vs.NEEC:42.4％ vs.72.8 ％,t=-6.897,P ＜ 0.001).In EEC,DNMT3A overexpression was significantly correlated with the hypermethylation and low expression of the ESR1 and PGR (P ＜ 0.05).The same trend was observed in the DNMT3B overexpression subgroup.In the ESR1/ PGR low-expression subgroups,as much as 83.1％ of ESR1 and 59.5％ of PGR were hypermethylated,which was significantly greater than the ESR1/PGR high-expression subgroups (31.3％ and 11.9％,respectively).However,the above phenomena were absent in NEEC,while DNMT3A/3B overexpression,ESR1/PGR hypermethylation,and low ER/PR expression occurred much more often.In univariate analysis,DNMT3A/3B overexpressions were significantly correlated with worse prognosis.In multivariate analysis,only DNMT3A was an independent predictor of disease-free survival (P ＜ 0.05).Conclusions:DNMT3A/3B expression increases progressively from EEC to NEEC and is correlated with poor survival.The mechanisms underlying low ER/PR expression might be distinct in EEC vs.NEEC.In EEC,methylation related to DNMT3A/3B overexpression might play a major role in ER/PR downregulation.