Relative leukocyte telomere length and the risk of lung cancer progression in individuals with pulmonary nodules

Abstract Background The role of leukocyte telomere length (LTL) in predicting lung cancer risk remains controversial, particularly in individuals with pulmonary nodules. Methods We conducted a prospective cohort study of 1803 individuals with pulmonary nodules identified by chest CT, with no prior history of cancer. Relative LTL (rLTL) was measured using quantitative PCR. Lung cancer incidence and mortality were ascertained through linkage with the Chongqing Chronic Disease Surveillance System using ICD-10 code. Associations between rLTL and lung cancer risk were assessed using Cox proportional hazards models, with adjustment for demographic, clinical, and radiological variables. We further evaluated the incremental predictive value of rLTL when added to five established lung nodule malignancy risk models using AUC, NRI, and IDI. Results Patients with longer rLTL had an increased risk of lung cancer (adjusted HR = 7.26 (1.71–30.87); P = 0.007), compared with those with shorter rLTL. Subgroup analyses suggested stronger associations in younger individuals and women, although interactions were non-significant. rLTL remained an independent predictor across all five lung nodule models (HR range, 1.47–1.72). While the improvements in AUC and IDI were modest, NRI was significantly improved in all models (range, 0.380–0.847, all P < 0.05), suggesting better risk reclassification. Conclusion In this health check-up cohort of individuals with pulmonary nodules, longer rLTL was independently associated with increased lung cancer risk. Our findings highlight a potentially paradoxical role of telomere biology in lung carcinogenesis and suggest that rLTL may serve as a useful biomarker for malignancy risk stratification in nodule surveillance.