Identification of Key Genes Involved in the Occurrence and Development of Endometrial Cancer.

OBJECT: Endometrial cancer (EC) is one of the most common gynecologic malignancies, for which endometrial hyperplasia (EH) and type 2 diabetes are established high-risk factors. However, the common molecular mechanisms underlying this association remain poorly understood. This study therefore aimed to identify and validate hub genes linking EH, type 2 diabetes, and EC, and to assess their prognostic value. METHODS: Intersection genes among EH and EC DEGs (GSE106191) and type 2 diabetes-related genes (GeneCards) were screened. A prognostic model was constructed via Lasso-Cox regression in TCGA-UCEC. Functional enrichment (GO and KEGG) analyzed the prognostic model. The PPI network identified hub genes within the prognostic model. Subsequent prognostic analysis in TCGA-UCEC validated key hub genes. Their expression was further analyzed across GSE106191 and TCGA-UCEC datasets and confirmed via immunohistochemistry. Correlations with clinical features (age, stage, grade, TP53 mutation, weight) in EC were assessed using UALCAN. RESULTS: One hundred and sixty-two intersection genes were identified. The 16-gene prognostic model stratified EC patients into high/low-risk groups with significantly distinct overall survival (HR = 3.475, P = 2.51e-7; 1/3/5-year AUCs: 0.740/0.749/0.783). Functional enrichment linked genes to TGF-beta signaling and estrogen pathways. Combined PPI network analysis and prognostic validation identified PGR and VIM as key hub genes, both significantly downregulated in EC versus normal tissues across TCGA-UCEC and GSE106191 datasets (P < 0.05; IHC confirmed). Notably, within tumor samples, PGR and VIM expression was significantly higher in EC patients with diabetes compared to those without diabetes. Immunohistochemistry confirmed the downregulation of PGR and VIM protein expression in EC tissues compared to normal and EH tissues. Their expression correlated with clinical characteristics (age, stage, histology, TP53 mutation, weight) and was elevated in diabetic EC patients (P < 0.05). CONCLUSION: PGR and VIM were identified as DEGs of EH, type 2 diabetes, and EC. Their reduced expression in EC correlated with poorer prognosis, underscoring their potential as prognostic biomarkers and therapeutic targets, especially in diabetic EC patients. In this study, we offer a new genetic biomarker for the prediction of EC patients' prognosis.