Association of telomere length with risk of lung cancer: A large prospective cohort study from the UK Biobank

•Longer leukocyte telomere length was associated with an elevated risk of lung cancer.•This association was stronger in subpopulations of females and nonsmokers.•The modification effect of smoking on the association of telomere length and lung cancer risk differed in histological subtypes.•The effect of leukocyte telomere length on lung cancer risk was modified by genetic susceptibility. Leukocyte telomere length (LTL) is associated with a wide variety of diseases, including cancer. However, findings regarding the association between LTL and the risk for lung cancer have been inconclusive and inconsistent across previous observational studies. This prospective cohort study included data from 425,146 participants 37–73 years of age housed in the UK Biobank. Quantitative polymerase chain reaction (qPCR) was used to measure LTL in baseline DNA samples. A multivariate Cox proportional hazards model was used to evaluate the relationship between LTL and the risk for lung cancer. An increase in LTL per interquartile range (IQR) was associated with a 9% increase in the risk for lung cancer (hazard ratio [HR] 1.09 [95% confidence interval (CI) 1.03–1.16]). Participants in the highest LTL quintile exhibited an approximately 25% elevated risk for developing lung cancer (HR 1.25 [95% CI 1.09–1.45]) compared with those in the lowest quintile. The relationship between per IQR increase in LTL and elevated risk for lung cancer was greater in the histological subtype of adenocarcinoma (HR 1.30 [95% CI 1.18–1.43]), female sex (HR 1.16 [95% CI 1.06–1.26]), non-smokers (HR 1.45 [95% CI 1.23–1.71]), and individuals with high genetic risk for lung cancer (HR 1.18 [95% CI 1.03–1.34]), respectively. Surprisingly, a per IQR increase in LTL was associated with increased risks for both lung adenocarcinoma (HR 1.56 [95% CI 1.24–1.96]) and squamous cell carcinoma (HR 2.01 [95% CI 1.13–3.56]) in never smokers. Longer LTL was associated with an elevated risk for lung cancer, particularly for adenocarcinoma and squamous cell carcinoma in never smokers. The results suggest the potential of telomeres as non-invasive biomarkers for the early screening of lung cancer, particularly in non-smokers, who are typically overlooked.