Abstract 2375: Investigating airway epithelial TP53 somatic mutation prevalence as a common risk factor for COPD and lung cancer

Abstract Background: Lung cancer (LC) and Chronic Obstructive Pulmonary Disease (COPD) are leading causes of morbidity and mortality both in the United States and worldwide. There is a high degree of association between COPD and LC, which is not well understood. Smoking is a risk factor for COPD, while both cigarette smoke and COPD are risk factors for LC. Approximately 10% of current smokers are at risk for developing COPD and every year an estimated 1% of COPD patients develop LC. We recently reported that in the airway epithelium of smokers, there is an increased prevalence of somatic TP53 mutations. Further, among heavy smokers TP53 mutation prevalence was associated with LC. Due to the known association between COPD and LC risk we investigated whether TP53 mutation prevalence in airway epithelium may be a common factor. Methods: Patients undergoing bronchoscopy were recruited into an IRB-approved research study wherein soft brushings of the large airways were collected. Bronchial brush specimens from 59 subjects were sequenced by PCR-amplicon library NGS. The TP53 biomarker was measured from 59 subjects, 30 LC and 29 non-LC. The non-LC group comprised 7 COPD and 22 non-COPD subjects. Using specialized internal standards to compensate for sequencing error, VAF was observable down to 0.01%. Results: The TP53 biomarker was associated (p<0.05) with COPD among all 59 subjects with 76% specificity, 62% sensitivity, positive predictive value (PPV) 59% and negative predictive value (NPV) 78%. When plotted on a receiver operator characteristic (ROC) curve the area under the curve (AUC) was 0.82. Notably, the TP53 biomarker was significantly associated with COPD among non-LC subjects, with 95% specificity, 57% sensitivity, PPV 80% and NPV 87.5%. When fit to an ROC curve, the AUC for the COPD cohort was 0.84 Conclusions: TP53 prevalence was associated with COPD diagnosis among both LC and non-LC patients in this small discovery set. We plan to validate the association in larger case-control studies. If validated, this biomarker may enable early detection of those at risk for COPD before the obstructive defect develops as well as those who should be prioritized for LC screening. We will also further investigate interindividual variation between which patients develop lung cancer and or without the background of COPD through the lens of the TP53 biomarker. Citation Format: Andrew Boring, Erin L. Crawford, Dan J. Craig, Heidi Chen, Rami Ahmad, Mohamed Omballi, Eric Grogan, Stephen Deppen, James C. Willey. Investigating airway epithelial TP53 somatic mutation prevalence as a common risk factor for COPD and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2375.