Identification of a Four-Gene Signature With Prognostic Significance in Endometrial Cancer Using Weighted-Gene Correlation Network Analysis

Abstract

Endometrial hyperplasia (EH) is a precursor for endometrial cancer (EC). However, biomarkers for the progression from EH to EC and standard prognostic biomarkers for EC have not been identified. In this study, we aimed to identify key genes with prognostic significance for the progression from EH to EC. Weighted-gene correlation network analysis (WGCNA) was used to identify hub genes utilizing microarray data (GSE106191) downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified from the Uterine Corpus Endometrial Carcinoma (UCEC) dataset of The Cancer Genome Atlas database. The Limma-Voom R package was applied to detect differentially expressed genes (DEGs; mRNAs) between cancer and normal samples. Genes with |log2 (fold change [FC])| > 1.0 and p < 0.05 were considered as DEGs. Univariate and multivariate Cox regression and survival analyses were performed to identify potential prognostic genes using hub genes overlapping in the two datasets. All analyses were conducted using R Bioconductor and related packages. Through WGCNA and overlapping genes in hub modules with DEGs in the UCEC dataset, we identified 42 hub genes. The results of the univariate and multivariate Cox regression analyses revealed that four hub genes, BUB1B, NDC80, TPX2, and TTK, were independently associated with the prognosis of EC (Hazard ratio [95% confidence interval]: 0.591 [0.382–0.912], p = 0.017; 0.605 [0.371–0.986], p = 0.044; 1.678 [1.132–2.488], p = 0.01; 2.428 [1.372–4.29], p = 0.02, respectively). A nomogram was established with a risk score calculated using the four genes’ coefficients in the multivariate analysis, and tumor grade and stage had a favorable predictive value for the prognosis of EC. The survival analysis showed that the high-risk group had an unfavorable prognosis compared with the low-risk group (p < 0.0001). The receiver operating characteristic curves also indicated that the risk model had a potential predictive value of prognosis with area under the curve 0.807 at 2 years, 0.783 at 3 years, and 0.786 at 5 years. We established a four-gene signature with prognostic significance in EC using WGCNA and established a nomogram to predict the prognosis of EC.