Abstract
Background: Telomere homeostasis serves as a key regulatory mechanism linking aging and cancer. While telomere attrition imposes a proliferative barrier by inducing cellular senescence, abnormal telomere elongation circumvents this constraint, thereby granting malignant cells unlimited replicative capacity. This study systematically explores the causal relationship between telomere length and cancer risk, with the goal of elucidating the molecular pathways involved in telomere-driven tumorigenesis. Method: Mendelian randomization (MR) was employed to establish a causal link between telomere length and pan-cancer susceptibility. Multiple MR models were employed to ensure the robustness of the results. Telomere-associated genes were identified through SNPense analysis, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Key gene regulatory networks were identified and visualized using the MCODE and cytoHubba algorithms. The expression profile of TERT across diverse cancer types was analyzed using TCGA datasets, and its diagnostic potential was evaluated via receiver operating characteristic (ROC) curve analysis. Correlations between TERT expression and immune cell infiltration were further explored. Results: Longer telomere length was significantly associated with an increased risk of 33 cancer types (IVW OR = 1.27-1.41, all P < 0.001). A total of 143 telomere-related genes were identified, with functional enrichment highlighting their involvement in genome integrity and telomere maintenance. TERT emerged as the most influential hub gene (MCC score = 169). Transcriptomic analyses from TCGA demonstrated widespread TERT overexpression in 16 cancers (e.g., CHOL, LIHC, LUAD), a finding corroborated by RT-qPCR validation. TERT exhibited high diagnostic performance (AUC > 0.85 in 16 cancers, peaking at AUC = 0.97 in LUSC). Immune infiltration analysis revealed a positive correlation with Th2 cells (r = 0.42) but negative correlations with dendritic cells (r = - 0.38) and macrophages (r = - 0.31). Conclusion: This study proposes a comprehensive framework linking telomere length regulation to cancer progression through the TERT axis. Telomere dysfunction contributes to tumorigenesis via two key mechanisms: promoting genomic instability and altering the immune microenvironment. These findings offer new insights into telomere-driven oncogenesis and lay a conceptual foundation for precision diagnostics and targeted therapies in oncology.