Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan

<jats:sec id="ab-zoi231146-4"><jats:title>Importance</jats:title><jats:p>Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs.</jats:p></jats:sec><jats:sec id="ab-zoi231146-5"><jats:title>Objectives</jats:title><jats:p>To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan.</jats:p></jats:sec><jats:sec id="ab-zoi231146-6"><jats:title>Design, Setting, and Participants</jats:title><jats:p>The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022.</jats:p></jats:sec><jats:sec id="ab-zoi231146-7"><jats:title>Exposures</jats:title><jats:p>A PRS was derived using 25 genetic variants that achieved genome-wide significance (<jats:italic>P</jats:italic> &amp;lt; 5 × 10<jats:sup>−8</jats:sup>) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work.</jats:p></jats:sec><jats:sec id="ab-zoi231146-8"><jats:title>Main Outcomes and Measures</jats:title><jats:p>The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure.</jats:p></jats:sec><jats:sec id="ab-zoi231146-9"><jats:title>Results</jats:title><jats:p>Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (<jats:italic>P</jats:italic> = 6.5 × 10<jats:sup>−4</jats:sup> for interaction) was identified.</jats:p></jats:sec><jats:sec id="ab-zoi231146-10"><jats:title>Conclusions and Relevance</jats:title><jats:p>This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.</jats:p></jats:sec>