Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan 20;132(2):161-170.
doi: 10.1097/CM9.0000000000000054.

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

Dan He  1 , Xiao Wang  2 , Yan Zhang  3 , Jian Zhao  3 , Rui Han  1 , Ying Dong  1
Affiliations

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

Dan He et al. Chin Med J (Engl). .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
DNMT3A/3B overexpressed in endometrial cancers and indicated a poor prognosis. (A) DNMT3A/3B overexpressed in EEC and was much higher in NEEC compared with normal controls. ∗P < 0.001 vs. normal controls or EEC. (B) The expression of DNMT3A and 3B was significantly positively correlated. (C and D) DNMT3A or DNMT3B overexpression correlated with poor survival and the combined two markers also implied unfavorable prognosis (e). DNMT3A/3B: DNA (cytosine-5)-methyltransferase 3A/3B; EEC: Endometrial endometrioid carcinoma; NEEC: Non-endometrial endometrioid carcinoma.
Figure 2
Figure 2
Hypermethylation (A) and reduced expression (B) of ESR1/PGR occurred more frequently in tumors with DNMT3A/3B overexpression compared with tumors without DNMT3A/3B overexpression in EEC; however, the phenomena were not present in NEEC. DNMT3A/3B: DNA (cytosine-5)-methyltransferase 3A/3B; EEC: Endometrial endometrioid carcinoma; ESR1: Estrogen receptor 1; NEEC: Non-endometrial endometrioid carcinoma; PGR: Progesterone receptor.
Figure 3
Figure 3
Hypermethylation or low expression of ESR1/PGR was correlated with poor survival. DNMT3A/3B: DNA (cytosine-5)-methyltransferase 3A/3B; EEC: Endometrial endometrioid carcinoma; ESR1: Estrogen receptor 1; NEEC: Non-endometrial endometrioid carcinoma; PGR: Progesterone receptor.
Figure 4
Figure 4
Combination of DNMT3A/3B overexpression with ESR1/PGR low expression and/or hypermethylation indicated poor prognosis in endometrial cancers. DNMT3A/3B: DNA (cytosine-5)-methyltransferase 3A/3B; ESR1: Estrogen receptor 1; PGR: Progesterone receptor.
See this image and copyright information in PMC

References

    1. Murali R, Soslow RA, Weigelt B. Classification of endometrial carcinoma: more than two types. Lancet Oncol 2014;15:e268–e278. doi: 10.1016/s1470-2045(13)70591-6. - PubMed
    1. Geels YP, Pijnenborg JM, van den Berg-van Erp SH, Bulten J, Visscher DW, Dowdy SC, et al. Endometrioid endometrial carcinoma with atrophic endometrium and poor prognosis. Obstet Gynecol 2012;120:1124–1131. - PubMed
    1. Hervouet E, Peixoto P, Delage-Mourroux R, Boyer-Guittaut M, Cartron PF. Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma. Clin Epigenet 2018;10:17 doi: 10.1186/s13148-018-0450-y. - PMC - PubMed
    1. Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005;74:481–514. doi: 10.1146/annurev.biochem.74.010904.153721. - PubMed
    1. Jia D, Jurkowska RZ, Zhang X, Jeltsch A, Cheng X. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 2007;449:248–251. doi: 10.1038/nature06146. - PMC - PubMed

MeSH terms

Substances