Polygenic Risk Score Is Associated with Developing and Dying from Lung Cancer in the National Lung Screening Trial

Area of Science:

• Genetics and Epidemiology
• Cancer Research
• Biomarker Discovery

Background:

• Lung cancer development is influenced by both smoking and genetic predisposition.
• Polygenic risk scores (PRS), aggregating effects of multiple genetic variants, offer potential for risk stratification.
• Clinical utility of PRS in lung cancer screening cohorts remains unexplored.

Purpose of the Study:

• To evaluate the association between a composite PRS and lung cancer incidence and mortality in a lung cancer screening population.
• To validate the PRS's predictive performance for lung cancer mortality in an independent cohort of ever-smokers.

Main Methods:

• Post hoc analysis of 9,191 high-risk smokers from the National Lung Screening Trial (NLST).
• Calculation of a composite PRS from 12 validated risk genotypes.
• Validation in the UK Biobank cohort (N=167,796) of unscreened ever-smokers.

Main Results:

• The PRS significantly correlated with lung cancer incidence (p < 0.0001) and mortality (p = 0.004) in the NLST cohort.
• Elevated PRS was independently associated with lung cancer death (p = 0.0027).
• Higher PRS scores (intermediate and high) were linked to increased lung cancer mortality rates compared to low PRS.
• The association between PRS and lung cancer mortality was confirmed in the UK Biobank cohort (p = 0.002).

Conclusions:

• An elevated polygenic risk score is an independent predictor of lung cancer mortality.
• PRS demonstrates utility as a biomarker for identifying individuals at higher risk of fatal lung cancer.
• Findings support the potential integration of PRS into lung cancer screening protocols.