TP53-mutated preneoplastic colonies, adaptive immune response, and risk for lung cancer and COPD

Our purpose was to better characterize the prevalence and size distributions of TP53-mutated preneoplastic colonies in relationship to risk for lung cancer (LC) and chronic obstructive pulmonary disease (COPD). Ultra-sensitive next-generation sequencing (US-NGS) was used to assess TP53-mutated preneoplastic colonies comprising as few as 100 cells in airway epithelium. Specimens from 59 subjects with heavy smoking history were assessed in four cohorts: LC with (N=14) or without COPD (N=16) and non-LC with (N=7) or without COPD (N=22). TP53-mutated preneoplastic colony prevalence was higher in LC subjects with or without COPD and in COPD subjects without LC (P<0.01). A higher prevalence of colonies driven by the subset of TP53 mutations known to be neoantigenic in cancer tissue was nominally significant (P<0.05). TP53-mutated colony distributions skewed to larger sizes among LC subjects and skewed greater among subjects with both COPD and active cigarette smoking (P<0.01), each of which is associated with adaptive immune inflammation. Thus, consistent with prior studies, TP53-mutated colony prevalence and size distribution measured in non-malignant airway epithelium improved characterization of LC and COPD risk. Further, these colonies may stimulate adaptive immune response and inflammation that is mechanistically associated with COPD. A skew to larger colonies is consistent with selection for immune surveillance avoidance characteristics and may provide a metric for both LC risk and immune surveillance function. Among healthier non-COPD smokers who are ineligible for lung cancer screening based on demographic criteria, a positive TP53 biomarker test may identify LC risk sufficiently high to warrant screening eligibility.