Development and Validation of a Telomere-Related Gene Signature in Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) is a highly malignant tumor with poor prognosis. Telomeres and their associated genes play critical roles in carcinogenesis, yet their systematic integration into a prognostic model for HCC requires further exploration. This study aimed to construct a robust prognostic signature based on telomere-related genes to improve risk stratification and therapeutic guidance for HCC patients. Methods Transcriptomic and clinical data were obtained from TCGA (369 HCC, 50 normal) and HCCDB (203 cases) databases. A comprehensive set of 2,093 telomere-related genes was acquired from TelNet. Hub genes were identified through integrated analysis using ssGSEA, WGCNA, and differential expression. A prognostic risk model was developed via univariate Cox, LASSO, and multivariate Cox regression analyses, with external validation performed. Results We established a six-gene prognostic signature (E2F1, MYCN, VPS72, CFAP53, OR8D1, TXNRD1) that effectively stratified patients into distinct risk groups. The high-risk group demonstrated significantly worse overall survival in both training and validation cohorts (p < 0.05). Multivariate analysis confirmed the risk score as an independent prognostic factor. Functional analysis revealed significant enrichment of DNA replication and cell cycle pathways in high-risk patients. Immune characterization showed distinct infiltration patterns and elevated immune evasion potential in the high-risk group. Drug sensitivity analysis identified potential therapeutic vulnerabilities to specific inhibitors. Conclusion The novel telomere-related six-gene signature provides reliable prognosis prediction, reflects tumor microenvironment characteristics, and offers insights for personalized treatment strategies in HCC, serving as a valuable tool for clinical decision-making.