High Tudor and KH domain-containing protein expression predicts poor prognosis and drug response in uterine corpus endometrial carcinoma: Insights from TCGA and GEO analyses

Abstract Background: Uterine corpus endometrial carcinoma (UCEC) is a common gynecologic malignancy; however, its molecular underpinnings remain incompletely defined. Recent studies have suggested that roles played by mitochondrial and RNA-processing proteins in cancer progression remain unknown. Tudor and KH domain-containing protein (TDRKH) is a mitochondrial protein previously associated with germline development and piRNA biogenesis; however, its role in endometrial cancer has not been explored. Objectives: This study aimed to investigate the expression profile, genomic alterations, clinical relevance, and therapeutic implications of TDRKH in UCEC. Methods: This retrospective bioinformatics study analyzed multi-omics data from The Cancer Genome Atlas (TCGA)–UCEC and Gene Expression Omnibus cohorts (GSE146889 and GSE17025) to evaluate TDRKH gene expression, copy-number variation, and prognostic value. Survival analysis was performed using Cox regression and Kaplan–Meier methods. To explore high TDRKH expression-associated biological pathways, gene set enrichment analysis (GSEA) was used. Drug sensitivity correlation analyses were conducted using IC50 profiles from public pharmacogenomic datasets. Results: TDRKH was amplified in 38% of UCEC cases and was among the top five most frequently amplified genes. Tumor tissues showed a significantly higher TDRKH mRNA expression than the normal endometrium across three datasets (TCGA–UCEC, GSE146889, and GSE17025). High TDRKH expression was independently associated with poor disease-free, progression-free, overall, and disease-specific survival. GSEA revealed enrichment of transcriptional regulation, DNA repair, and RNA export pathways in TDRKH-high tumors. Drug response analysis revealed that high TDRKH expression was correlated with resistance to docosanol and olprinone, but sensitivity to cefixime and ethionamide. Conclusion: TDRKH is frequently amplified and overexpressed in UCEC and may serve as a robust prognostic marker. Its expression is associated with specific oncogenic pathways and drug response profiles, suggesting that TDRKH is a potential biomarker and therapeutic target in endometrial carcinoma.