Lung cancer and tobacco use pose significant global health challenges and require a comprehensive translational roadmap for improved prevention strategies. We propose the GREAT care paradigm (Genomic Informed Care for Motivating High Risk Individuals Eligible for Evidence-based Prevention), which employs polygenic risk scores (PRSs) to stratify disease risk and personalize interventions, such as lung cancer screening and tobacco treatment. We developed PRSs using large-scale multi-ancestry genome-wide association studies and adjusted for genetic ancestry for standardized risk stratification across diverse populations. We applied our PRSs to over 340,000 individuals of diverse ethnic background and found significant odds ratios for lung cancer and difficulty quitting smoking. These findings enable the evaluation of PRS-based interventions in ongoing trials aimed at motivating health behavior changes in high-risk patients. This pioneering approach enhances primary care with genomic insights, promising improved outcomes in cancer prevention and tobacco treatment, and is currently under assessment in clinical trials.

Laura J. Bierut is listed as an inventor on Issued U.S. Patent 8,080,371, "Markers for Addiction" covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Michael J. Bray is an employee at ThinkGenetic, Inc. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. All other authors have no conflict of interests to report.

This research was supported by NIH Training Grant T32GM135117 and NSF Graduate Research Fellowship DGE-2140743 (T.C.), R35-3CA197449, R01-HL163560, U01-HG009088, and U01-HG012064 (X.L.), NIH Intramural Research Program (H.Z.), NIH 5T32-HL007776-25, R01-DA056050, R01-CA268030, P30-CA091842-19S5, P30-CA091842-16S2 and P50-CA244431 (L.C.) and U19-CA203654.

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