Abstract
Background Survival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed.
Methods Large-format tissue samples from a prospective cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL and FVIII, and were followed for a median of 2.34 (95% CI 1.71–3.49) years.
Results Unsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathological features and genotype, but with markedly different survival: “proliferative” patients (60%) with elevated TP53, NF1, CD45 and PCNA expression had 50% 5-year overall survival, while “apoptotic” patients (40%) with high TUNEL had 70% 5-year survival (hazard ratio 2.23, 95% CI 1.33–3.80; p=0.0069). Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in The Cancer Genome Atlas and KMplotter data, and showed prognostic power supplementary to International Association for the Study of Lung Cancer tumour–node–metastasis stage and World Health Organization histologic classification.
Conclusions Two molecular subtypes of LUAD exist and their identification provides important prognostic information.
Abstract
Clinical-grade immunodetection of TP53, NF1, CD45, PD-1, PCNA, TUNEL and FVIII in tumour samples identifies two phenotypes of resected lung adenocarcinomas that display different prognosis and can be used for patient management and trial design https://bit.ly/3DpM5Ll
Footnotes
Author contributions: M. Lindner, I. Koch and R.A. Hatz performed surgeries and procured data that were produced during surgeries. J. Behr performed clinical and physiological assessment. M.A.A. Pepe, M. Spella, I. Lilis, G. Ntaliarda, S.J. Behrend, G.A. Giotopoulou and A.C. Schamberger processed samples and provided important intellectual input. A-S. Lamort and W. Kujawa performed IHC. M.A.A. Pepe performed digital droplet PCR and analysed data; K. Somogyi and R. Sotillo analysed ALK fusions. A-S. Lamort, J.C. Kaiser and G.T. Stathopoulos designed and guided the study, analysed data, and wrote the manuscript. All authors critically reviewed and edited the paper for important intellectual content and approved the final submitted version. A-S. Lamort, J.C. Kaiser and G.T. Stathopoulos had full access to all the data of the study, had final responsibility for the decision to submit it for publication and are the guarantors of the study's integrity.
This article has an editorial commentary: https://doi.org/10.1183/13993003.00569-2022
This study is registered at the German Clinical Trials Register with identifier number DRKS00012649.
Conflict of interest: The authors declare no potential conflicts of interest.
Support statement: This work was supported by European Research Council 2010 Starting Independent Investigator (260524) and 2015 Proof of Concept (679345) grants, the Graduate College (Graduiertenkolleg) 2338 of the German Research Society (Deutsche Forschungsgemeinschaft), the target validation project for pharmaceutical development ALTERNATIVE of the German Ministry for Education and Research (Bundesministerium für Bildung und Forschung), and a Translational Research Grant by the German Center for Lung Research (Deutsches Zentrum für Lungenforschung) (all to G.T. Stathopoulos). The study sponsors had no role in study design, data collection, analysis and interpretation, and in writing and submitting the paper for publication. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 14, 2021.
- Accepted November 11, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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