TP53-Mutated Preneoplastic Colonies, Adaptive Immune Response, and Risk for Lung Cancer and COPD
4 affiliations
- 1The University of Toledo College of Medicine, Toledo, Ohio.
- 2University of New Mexico, Albuquerque, New Mexico.
- 3Vanderbilt University Medical Center, Nashville, Tennessee.
- 4Promedica, Toledo, Ohio.
Abstract
The purpose of this study was to better characterize the prevalence and size distributions of TP53-mutated preneoplastic colonies in relation to the risk for lung cancer and chronic obstructive pulmonary disease (COPD). Ultrasensitive next-generation sequencing was used to assess colonies comprising as few as 100 cells in airway epithelium. Specimens from 59 subjects with a heavy smoking history were assessed in four cohorts: lung cancer with (n = 14) or without COPD (n = 16) and non–lung cancer with (n = 7) or without COPD (n = 22). TP53-mutated preneoplastic colony prevalence was higher in lung cancer subjects with or without COPD and in COPD subjects without lung cancer (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 lung cancer 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, TP53-mutated colony prevalence and size distribution measured in nonmalignant airway epithelium improved characterization of lung cancer and COPD risk. Further, these colonies may stimulate the 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 lung cancer 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 lung cancer risk sufficiently high to warrant screening eligibility.
Prevention Relevance:: TP53-mutated colony prevalence and size distribution measured in nonmalignant airway epithelium improved characterization of lung cancer and COPD risk. The observed skew to larger colonies in lung cancer subjects is consistent with selection for immune surveillance avoidance and may enable measurement of immune surveillance function to guide the development of prevention therapeutics.
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BibTeX
@article{willey2026tp53mutated,
title = {{TP53-Mutated Preneoplastic Colonies, Adaptive Immune Response, and Risk for Lung Cancer and COPD}},
author = {James C. Willey and Andrew R. Boring and Erin L. Crawford and Kevin N. Lei and Thomas M. Blomquist and Christopher I. Amos and Stephen A. Deppen and Eric L. Grogan and Heidi Chen and Mohamed Omballi and Daniel J. Craig},
journal = {Cancer Prevention Research (Philadelphia, Pa.)},
year = {2026},
month = jul,
doi = {10.1158/1940-6207.capr-26-0112},
url = {https://doi.org/10.1158/1940-6207.capr-26-0112},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - TP53-Mutated Preneoplastic Colonies, Adaptive Immune Response, and Risk for Lung Cancer and COPD
AU - James C. Willey
AU - Andrew R. Boring
AU - Erin L. Crawford
AU - Kevin N. Lei
AU - Thomas M. Blomquist
AU - Christopher I. Amos
AU - Stephen A. Deppen
AU - Eric L. Grogan
AU - Heidi Chen
AU - Mohamed Omballi
AU - Daniel J. Craig
PY - 2026
DA - 2026/07/23
JO - Cancer Prevention Research (Philadelphia, Pa.)
DO - 10.1158/1940-6207.capr-26-0112
UR - https://doi.org/10.1158/1940-6207.capr-26-0112
AB - The purpose of this study was to better characterize the prevalence and size distributions of TP53-mutated preneoplastic colonies in relation to the risk for lung cancer and chronic obstructive pulmonary disease (COPD). Ultrasensitive next-generation sequencing was used to assess colonies comprising as few as 100 cells in airway epithelium. Specimens from 59 subjects with a heavy smoking history were assessed in four cohorts: lung cancer with (n = 14) or without COPD (n = 16) and non–lung cancer with (n = 7) or without COPD (n = 22). TP53-mutated preneoplastic colony prevalence was higher in lung cancer subjects with or without COPD and in COPD subjects without lung cancer (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 lung cancer 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, TP53-mutated colony prevalence and size distribution measured in nonmalignant airway epithelium improved characterization of lung cancer and COPD risk. Further, these colonies may stimulate the 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 lung cancer 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 lung cancer risk sufficiently high to warrant screening eligibility. Prevention Relevance:: TP53-mutated colony prevalence and size distribution measured in nonmalignant airway epithelium improved characterization of lung cancer and COPD risk. The observed skew to larger colonies in lung cancer subjects is consistent with selection for immune surveillance avoidance and may enable measurement of immune surveillance function to guide the development of prevention therapeutics.
SN - 1940-6207
SN - 1940-6215
ER -