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基于DNA甲基化驱动基因的子宫内膜癌患者潜在预后生物标志物的开发

Development of Potential Prognostic Biomarkers Based on DNA Methylation-Driven Genes for Patients with Endometrial Cancer.

作者信息

Lu Yiling, Tang Weichun, Wang Xiaoyu, Kang Xinyi, You Jun, Chen Liping

机构信息

Department of Obstetrics and Gynecology, Nantong First People's Hospital, Nantong, Jiangsu, 226001, People's Republic of China.

NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu, 211166, People's Republic of China.

出版信息

Int J Gen Med. 2021 Dec 31;14:10541-10555. doi: 10.2147/IJGM.S341771. eCollection 2021.

DOI:10.2147/IJGM.S341771
PMID:35002309
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8725853/
Abstract

BACKGROUND: Endometrial cancer (EC) is a multifactorial disease, and its progression may be driven by abnormal genetic methylation. To clarify the underlying molecular mechanisms and sensitive biomarkers for EC, this study used an integrated bioinformatic analysis to explore the methylation-driven genes of EC. METHODS: The mRNA expression data, methylation data and corresponding clinical information of EC samples were downloaded from The Cancer Genome Atlas (TCGA) database. MethylMix algorithm was used to screen out methylation-driven genes in EC. Functional and pathway enrichment analysis and the protein-protein interaction (PPI) analysis were conducted to demonstrate the functions and interactions between these genes. Then, prognosis-related methylated genes were screened out by using univariate and multivariate Cox analyses, and a prognostic risk assessment model for EC was constructed. The methylation sites and expression profiles of candidate genes were further investigated. RESULTS: A total of 127 methylated genes were identified in EC. Four genes (RP11-968O1.5, DCAF12L1, MSX1 and ALS2CR11) were selected as candidate genes to construct a reliable prognostic risk model. The univariate and multivariate Cox proportional hazards regression analyses showed that the risk score based on four genes was an independent prognostic indicator for OS among EC patients. A nomogram was established and the calibration plot analysis indicated the good performance and clinical utility of the nomogram. In addition, the methylation and expression of MSX1 and DCAF12L1 were significantly associated with EC survival rate. The joint ROC analysis revealed that the AUC of DCAF12L1-MSX1 was 0.867, which suggested both have a good EC-diagnosing efficiency. We then coped DCAF12L1 and MSX1 with GESA analysis, finding both were mainly associated with the KRAS signaling pathway. CONCLUSION: This bioinformatic study combs the methylated genes involved in EC development for the first time, finding that MSX1 and DCAF12L1 could serve as EC prognostic markers and drug targets.

摘要

背景：子宫内膜癌（EC）是一种多因素疾病，其进展可能由异常的基因甲基化驱动。为阐明EC潜在的分子机制和敏感生物标志物，本研究采用综合生物信息学分析来探索EC的甲基化驱动基因。 方法：从癌症基因组图谱（TCGA）数据库下载EC样本的mRNA表达数据、甲基化数据及相应临床信息。使用MethylMix算法筛选出EC中的甲基化驱动基因。进行功能和通路富集分析以及蛋白质-蛋白质相互作用（PPI）分析，以证明这些基因之间的功能和相互作用。然后，通过单因素和多因素Cox分析筛选出与预后相关的甲基化基因，并构建EC的预后风险评估模型。进一步研究候选基因的甲基化位点和表达谱。 结果：在EC中总共鉴定出127个甲基化基因。选择四个基因（RP11 - 968O1.5、DCAF12L1、MSX1和ALS2CR11）作为候选基因构建可靠的预后风险模型。单因素和多因素Cox比例风险回归分析表明，基于这四个基因的风险评分是EC患者总生存期的独立预后指标。建立了列线图，校准曲线分析表明列线图具有良好的性能和临床实用性。此外，MSX1和DCAF12L1的甲基化和表达与EC生存率显著相关。联合ROC分析显示，DCAF12L1 - MSX1的AUC为0.867，表明两者都具有良好的EC诊断效率。然后我们对DCAF12L1和MSX1进行基因集富集分析（GESA），发现两者主要与KRAS信号通路相关。 结论：本生物信息学研究首次梳理了参与EC发生发展的甲基化基因，发现MSX1和DCAF12L1可作为EC的预后标志物和药物靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/c7f9cecc0830/IJGM-14-10541-g0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/c31fcba1022b/IJGM-14-10541-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/968c1fe29794/IJGM-14-10541-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/83f792fe198b/IJGM-14-10541-g0003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/27490ebac4ff/IJGM-14-10541-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/44b76d24eec0/IJGM-14-10541-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/7b2547febf17/IJGM-14-10541-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/d343228af0a2/IJGM-14-10541-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/57781706a428/IJGM-14-10541-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/c7f9cecc0830/IJGM-14-10541-g0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/c31fcba1022b/IJGM-14-10541-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/968c1fe29794/IJGM-14-10541-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/83f792fe198b/IJGM-14-10541-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/eacb13d59cf2/IJGM-14-10541-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/27490ebac4ff/IJGM-14-10541-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/44b76d24eec0/IJGM-14-10541-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/7b2547febf17/IJGM-14-10541-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/d343228af0a2/IJGM-14-10541-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/57781706a428/IJGM-14-10541-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1661/8725853/c7f9cecc0830/IJGM-14-10541-g0010.jpg

相似文献

[1]
Development of Potential Prognostic Biomarkers Based on DNA Methylation-Driven Genes for Patients with Endometrial Cancer.

Int J Gen Med. 2021-12-31

[2]
Identification of aberrantly methylated differentially expressed genes and associated pathways in endometrial cancer using integrated bioinformatic analysis.

Cancer Med. 2020-5

[3]
Establishment and validation of a prognostic nomogram based on a novel five-DNA methylation signature for survival in endometrial cancer patients.

Cancer Med. 2021-1

[4]
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Ann Transl Med. 2020-3

[5]
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Cancer Cell Int. 2021-7-10

[6]
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Front Genet. 2021-9-9

[7]
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Cancer Cell Int. 2019-9-5

[8]
Methylation-driven genes and their prognostic value in cervical squamous cell carcinoma.

Ann Transl Med. 2020-7

[9]
Identification of molecular markers associated with the progression and prognosis of endometrial cancer: a bioinformatic study.

Cancer Cell Int. 2020-2-19

[10]
LAT, HOXD3 and NFE2L3 identified as novel DNA methylation-driven genes and prognostic markers in human clear cell renal cell carcinoma by integrative bioinformatics approaches.

J Cancer. 2019-10-22

引用本文的文献

[1]
Explore the alterations of downstream molecular pathways caused by ARID1A mutation/knockout in human endometrial cancer cells.

J Cancer Res Clin Oncol. 2023-12

[2]
Screening and validation of potential markers associated with uterine corpus endometrial carcinoma and polycystic ovary syndrome based on bioinformatics methods.

Front Mol Biosci. 2023-6-9

[3]
MSX1-expression during the different phases in healthy human endometrium.

Arch Gynecol Obstet. 2023-7

本文引用的文献

[1]
Clinical Activity and Safety of the Anti-Programmed Death 1 Monoclonal Antibody Dostarlimab for Patients With Recurrent or Advanced Mismatch Repair-Deficient Endometrial Cancer: A Nonrandomized Phase 1 Clinical Trial.

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