Identification of prognosis markers for endometrial cancer by integrated analysis of DNA methylation and RNA-Seq data

Huo, Xiao; Sun, Hengzi; Cao, Dongyan; Yang, Jiaxin; Peng, Peng; Yu, Mei; Shen, Keng

doi:10.1038/s41598-019-46195-8

Cited by 26 publications

(16 citation statements)

References 44 publications

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“…This further reinforces the fundamental involvement of TTAGPs in cellular division. Our findings are further validated by the identification of hub genes CCNA2, CDK1, AURKA and CCNB1 in the network of DEGs between EC and normal tissue, which are consistent with previous studies [ 118 , 119 , 120 , 121 , 122 ]. Therefore, it is not surprising that many of the identified hub genes have already been implicated in EC.…”

Section: Discussionsupporting

confidence: 92%

“…EZH2 has been reported to interact with TERF2 and TERF2IP [ 131 ], of the shelterin complex, and also telomeric repeat-containing RNA ( TERRA ) [ 132 , 133 ]. In our survival analysis, AURKA and CCNA2 were identified as markers of unfavourable prognosis ( Table S34 ), which is supported by previous immunohistochemical studies [ 122 , 134 ]. Polymorphisms within the RAD51 gene have been associated with EC progression and recurrence [ 135 , 136 ].…”

Section: Discussionsupporting

confidence: 87%

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Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Bradfield

Button

Hill

et al. 2020

MPs

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Endometrial cancer (EC) is the commonest gynaecological malignancy. Current prognostic markers are inadequate to accurately predict patient survival, necessitating novel prognostic markers, to improve treatment strategies. Telomerase has a unique role within the endometrium, whilst aberrant telomerase activity is a hallmark of many cancers. The aim of the current in silico study is to investigate the role of telomere and telomerase associated genes and proteins (TTAGPs) in EC to identify potential prognostic markers and therapeutic targets. Analysis of RNA-seq data from The Cancer Genome Atlas identified differentially expressed genes (DEGs) in EC (568 TTAGPs out of 3467) and ascertained DEGs associated with histological subtypes, higher grade endometrioid tumours and late stage EC. Functional analysis demonstrated that DEGs were predominantly involved in cell cycle regulation, while the survival analysis identified 69 DEGs associated with prognosis. The protein-protein interaction network constructed facilitated the identification of hub genes, enriched transcription factor binding sites and drugs that may target the network. Thus, our in silico methods distinguished many critical genes associated with telomere maintenance that were previously unknown to contribute to EC carcinogenesis and prognosis, including NOP56, WFS1, ANAPC4 and TUBB4A. Probing the prognostic and therapeutic utility of these novel TTAGP markers will form an exciting basis for future research.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 87%

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Bradfield

Button

Hill

et al. 2020

MPs

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“…CDC20, in cooperation with other factors, has been reported to be an important modulator of the cell cycle and is associated with advanced tumor stages and higher grades in multiple cancer types, including pancreatic (58), breast (59) and colorectal cancer (60). A previous study suggested that low CDC20 expression is associated with an improved OS rate and that knockdown of CDC20 expression suppresses proliferation of EC cells (61).…”

Section: Discussionmentioning

confidence: 99%

Identification of a five‑gene signature for predicting the progression and prognosis of stage I endometrial carcinoma

et al. 2020

Oncol Lett

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Uterine corpus endometrial carcinoma (UCEC) is often diagnosed at an early clinical stage based on abnormal vaginal bleeding. However, the prognosis of UCEC is poor. The present study was conducted to identify novel tumor grade-related genes with the potential to predict the prognosis and progression of UCEC. A total of three gene expression microarray datasets were downloaded from the Gene Expression Omnibus database, and one RNA-sequencing dataset with corresponding clinical information of patients with UCEC was obtained from The Cancer Genome Atlas database. In summary, 1,447 differentially expressed genes (DEGs) were identified between endometrial cancerous tissues and normal endometrial tissues. Weighted gene co-expression network analysis was performed to assess the associations between DEGs and clinical traits. In total, five genes were found to be highly associated with the tumorigenesis and prognosis of UCEC. Among them, BUB1 mitotic checkpoint serine/threonine kinase B, cyclin B1, cell-division cycle protein 20 and non-SMC condensing I complex subunit G were involved in cell cycle regulation pathways, and DLG-associated protein 5 was involved in the Notch receptor 3 signaling pathway based on functional enrichment analyses. Of the five genes, four were highly expressed in endometrial cancerous tissues compared with normal endometrial tissues at the protein level. In addition, the higher expression of these genes predicted a higher tumor grade and worse overall survival. In conclusion, the present study revealed a 5-gene signature that can be used to predict the progression of UCEC.

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“…The epigenetic profile of tumor epithelial cells and their associated microenvironment are currently being explored in other tumor models such as prostate and breast cancer [18,19]. Although the epigenetic landscape has been investigated in endometrial cancer [20][21][22][23][24], there is limited analysis independently examining epithelial and stromal compartments.…”

Section: Introductionmentioning

confidence: 99%

Expression of Stromal Progesterone Receptor and Differential Methylation Patterns in the Endometrium May Correlate with Response to Progesterone Therapy in Endometrial Complex Atypical Hyperplasia

Neal

Núñez²,

Lai

et al. 2020

Reprod. Sci.

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Progesterone therapy is a viable treatment for complex atypical hyperplasia (CAH) and endometrial adenocarcinoma, though reliable molecular determinants of response are not available. To explore if analysis of pre-therapy endometrial biopsies could yield biomarkers of response to progesterone, patients with CAH or adenocarcinoma undergoing treatment with progestins were included in this cross-sectional study. Immunohistochemistry for progesterone receptor (PR) was performed. Manual PR expression scores (PRES) were first calculated for biopsies by counting PR-positive nuclei in 12 sensitive vs 9 resistant samples. Significant differences in manual PRES were detected in the stroma (p < 0.01) and total endometrium (p < 0.01) for sensitive vs resistant patients. Manual PRES in the stroma had the highest accuracy in segregating sensitive vs resistant patients (96%). Differences in epithelial PRES were not significant. To validate these findings, a correlation between manual PRES and visual PRES was performed in the 21 patients. An additional 11 patients were analyzed to test if visual PRES would be predictive of response to progesterone. Visual PRES in epithelia and stroma in the 32 specimens was calculated. Significant differences in visual PRES were detected in the stroma for sensitive vs resistant samples (p < 0.01), while differences in epithelial and total endometrium were not significant. Whole genome bisulfite sequencing was performed on DNA isolated using pre-therapy biopsies from 6 sensitive and 6 resistant patients in this cohort. Differentially methylated regions were identified in the stroma and epithelium when evaluating sensitive vs resistant samples. Pathways involved in cell adhesion demonstrated the greatest difference in methylation in these samples.

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Identification of prognosis markers for endometrial cancer by integrated analysis of DNA methylation and RNA-Seq data

Cited by 26 publications

References 44 publications

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Identification of a five‑gene signature for predicting the progression and prognosis of stage I endometrial carcinoma

Expression of Stromal Progesterone Receptor and Differential Methylation Patterns in the Endometrium May Correlate with Response to Progesterone Therapy in Endometrial Complex Atypical Hyperplasia

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