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DNMT3A/3B overexpression might be correlated with poor patient survival, hypermethylation and low expression of ESR1/PGR in endometrioid carcinoma: an analysis of The Cancer Genome Atlas

查看全文 作　　者：Dan [1]He;Xiao [2]Wang;Yan [3]Zhang;Jian [3]Zhao;Rui [1]Han;Ying [1]Dong 高影响力作者 机构地区：[1]Department of Pathology,Peking University First Hospital,Beijing 100034,China;[2]Institute of Systems Biomedicine,School of Basic Medical Sciences,Peking University Health Science Center,Beijing 100191,China;[3]Department of Gynecology and Obstetrics,Peking University First Hospital,Beijing 100034,China高影响力机构 出　　处：《Chinese Medical Journal》索引2019年第2期,共10页高影响力期刊 基　　金：a grant from the National Natural Science Foundation of Ghina (No.81360381). 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. 关 键 词：DNA (cytosine-5)-methyltransferase 3A/3B ESTROGENS RECEPTOR Progesterone RECEPTOR Endometrial carcinoma The Cancer Genome ATLAS
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