• Faculty of Medical and Health Sciences, University of Auckland, Auckland P.O. Box 37-971, New Zealand.
• Department of Applied Health Research, University College London, London WC1E6B1, UK.
• Department of Biostatistics and Centre for Biostatistics and Health Data Science, Brown University of Public Health, Providence, RI 02912, USA.
• Natera Inc., Austin, TX 78753, USA.
• Department of Radiological Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

Background: Epidemiological studies suggest lung cancer results from the combined effects of smoking and genetic susceptibility. The clinical application of polygenic risk scores (PRSs), derived from combining the results from multiple germline genetic variants, have not yet been explored in a lung cancer screening cohort. Methods: This was a post hoc analysis of 9191 non-Hispanic white subjects from the National Lung Screening Trial (NLST), a sub-study of high-risk smokers randomised to annual computed tomography (CT) or chest X-ray (CXR) and followed for 6.4 years (mean). This study's primary aim was to examine the relationship between a composite polygenic risk score (PRS) calculated from 12 validated risk genotypes and developing or dying from lung cancer during screening. Validation was undertaken in the UK Biobank of unscreened ever-smokers (N = 167,796) followed for 10 years (median). Results: In this prospective study, we found our PRS correlated with lung cancer incidence (p < 0.0001) and mortality (p = 0.004). In an adjusted multivariable logistic regression analysis, PRS was independently associated with lung cancer death (p = 0.0027). Screening participants with intermediate and high PRS scores had a higher lung cancer mortality, relative to those with a low PRS score (rate ratios = 1.73 (95%CI 1.14-2.64, p = 0.010) and 1.89 (95%CI 1.28-2.78, p = 0.009), respectively). This was despite comparable baseline demographics (including lung function) and comparable lung cancer characteristics. The PRS's association with lung cancer mortality was validated in an unscreened cohort from the UK Biobank (p = 0.002). Conclusions: In this biomarker-based cohort study, an elevated PRS was independently associated with dying from lung cancer in both screening and non-screening cohorts.