Telomere length promotes colorectal cancer through dual parallel pathways involving growth signaling and protein metabolism

作者：C. -J. Liu, Fang Wang, Zhen Zhang, Qiang Su, Yifeng Li · 发表于：Tropical Medicine and Health · 年份：2025 · DOI：10.1186/s41182-025-00854-x · 被引用次数：2 · 研究领域：Telomeres, Telomerase, and Senescence、Epigenetics and DNA Methylation、Birth, Development, and Health

BACKGROUND: While telomeres traditionally protect against cancer through genomic stability, recent evidence suggests a paradoxical association with increased malignancy risk. This study employed comprehensive Mendelian randomization (MR) to investigate the causal relationship between telomere length (TL) and colorectal cancer (CRC) risk and elucidate the underlying biological mechanisms through systematic mediation analysis. METHODS: We performed two-sample MR using genetic instruments from large-scale genome-wide association studies (GWASs). CRC data were obtained from FinnGen R12 (discovery cohort: 11,790 cases and 378,749 controls) and the GWAS Catalog (replication cohort: 19,948 cases and 12,124 controls). The inverse-variance weighted method served as the primary analysis, complemented by MR‒Egger, weighted median, and MR-PRESSO sensitivity analyses. The multivariable MR was adjusted for body mass index (BMI), processed meat intake, inflammatory bowel disease (IBD), and colorectal polyps. Two-step mediation analysis investigated 35 blood and urine biomarkers as potential mediators, with colocalization analysis performed to distinguish linkage from pleiotropy. RESULTS: Genetically predicted longer telomeres were consistently positively associated with increased CRC risk across both cohorts (discovery: odds ratio [OR] = 1.282, 95% confidence interval [CI] 1.126-1.459, P < 0.001; replication: OR = 1.253, 95% CI 1.067-1.472, P = 0.006). This association remained robust acros...