Precision risk stratification for lung cancer in COPD: Evidence from the All of Us Program.

Abstract

10537 Background: Chronic obstructive pulmonary disease (COPD) is a well-established independent risk factor for lung cancer, yet determinants of cancer susceptibility within this high-risk population remain incompletely characterized. Identifying clinical and genomic predictors is essential to improve risk stratification, early detection, and precision prevention strategies. Methods: We conducted an age-matched case–control study using de-identified data from the All of Us Research Program to evaluate sociodemographic characteristics, comorbidities, and genetic variants associated with lung cancer risk among adults with COPD. Baseline characteristics were summarized using descriptive statistics. Multivariable logistic regression was used to estimate adjusted odds ratios (AORs) controlling for relevant confounders. Genome-wide association studies (GWAS) were performed with rigorous quality control, population stratification adjustment, and correction for multiple testing. Results: Among 633,540 participants, 26,570 (4.2%) had COPD, including 2,044 (7.7%) with lung cancer. The mean age was 67.5 ± 11.4 years; 43.4% were male. In multivariable analysis, Asian ancestry was associated with increased lung cancer risk (AOR 2.25, 95% CI 1.55–3.26). Age 66–95 years conferred a 29% higher risk, and family history of lung cancer increased risk by 34% (95% CI 1.15–1.57). Hypothyroidism (AOR 1.58, 95% CI 1.27–1.97) and hyperlipidemia (AOR 1.32, 95% CI 1.04–1.68) were independently associated with lung cancer. GWAS identified 19 variants significantly associated with lung cancer risk, including rs539223166, rs551676206, rs922466204, rs144626313, rs147989022, and rs74502961. Conclusions: Distinct clinical and genetic factors contribute to lung cancer susceptibility among individuals with COPD. Integrating these determinants may enhance risk prediction and inform targeted surveillance strategies.