Daniel J. Craig

Supplementary Figure S1. Effect of upper limit of colony size on ROC AUC

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.

Supplementary Table S1. Subject Data

Supplementary Table S3. TP53 mutation-type enrichment in lung cancer tissue vs preneoplastic colonies

Supplementary Table S2. TP53 mutation type data

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.

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, 31, 33, 45, 53, 58). Advanced-stage and recurrent cervical cancers are typically lethal and have been the focus in recent years of the integration of immune checkpoint inhibitors (CPIs) to improve survival. We have consolidated information regarding the role of the immune system in both disease progression and disease clearance with the aid of targeted therapies and immunotherapeutic agents. Additionally, we have characterized the treatment modalities currently indicated as the standard of care—such as bevacizumab and the immune CPIs—and those recently approved or in development, including Tivdak, Vigil, and chimeric antigen receptor (CAR) T-cells.