Abstract Background: We previously identified a biomarker for the early detection of lung cancer (LC) based on the prevalence of TP53-mutated colonies in airway epithelium, and determined that this biomarker performs well in subjects with or without COPD. To better understand the biological basis for this biomarker, we compared TP53-mutated colony size distributions in subjects with or without COPD and/or LC. Methods: Airway epithelial cell specimens were collected from subjects undergoing bronchoscopy under an IRB-approved research protocol. DNA was extracted from each specimen and ultra-sensitive NGS was used to measure TP53 mutations, with variant allele fraction (VAF) as low as 0.01%. TP53-mutated colony size was estimated assuming cells were heterozygous for the mutation. Specimens from 59 subjects were assessed in four cohorts: lung cancer with COPD LC-CO) (N=14), non-lung cancer with COPD (NLC-CO) (N=7), lung cancer without COPD (LC-NCO) (N=16) and non-lung cancer without COPD (NLC-NCO) (N=22). Colony size distributions were assessed by piecemeal slope analysis and Kaplan-Meier analysis. Results: A total of 192 unique TP53 mutations were identified among the 59 subjects, distributed among the cohorts as follows: LC-CO, 72; NLC-C0, 19; LC-NCO, 87; and NLC-NCO, 14. The mutation VAF values ranged from 0.01% (0.0001) to 6% (0.06), corresponding to a TP53-mutated colony size range of 200 to 30,000 cells. For each cohort, colony prevalence was inversely proportional to colony size, and there was an inflection point (IP1) at 400-600 cells/colony. Prior to IP1 there was little change in colony number relative to size; after IP1 the decline had a steep slope. The IP1 value was smaller for CO subjects (400 cells) than for NCO subjects (600 cells). There was a second inflection point (IP2) at about 1,800 cells, after which there were few surviving colonies for NLC subjects, but many surviving colonies for LC subjects. According to Kaplan-Meier analysis, among LC-CO subjects the higher prevalence of colonies 1,800 cells in LC was key to accuracy of the TP53 biomarker. In contrast for LC-NCO subjects there was a higher prevalence of colonies across the range of sizes. Conclusions: Interactions between TP53 mutated colonies and the microenvironment are different in CO vs non-CO subjects. This difference may be partly due to the increased adaptive immune inflammation characteristic of CO lung tissue. Citation Format: James C. Willey, Andrew Boring, Erin L. Crawford, Daniel J. Craig, Chen Heidi, Rami Ahmad, Kevin Lei, Mohamed Omballi, Stephen A. Deppen, Eric Grogan, Thomas M. Blomquist. Effect of COPD diagnosis on TP53-mutated colony size distribution in airway epithelium of subjects with or without lung cancer [abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2528.
Willey et al. (Fri,) studied this question.