Anne-Sophie Lamort1,2,3, Jan Christian Kaiser4,3, Mario A A Pepe1,2, Ioannis Lilis5, Giannoula Ntaliarda5, Kalman Somogyi2,6, Magda Spella5, Sabine J Behrend1,2, Georgia A Giotopoulou1,2, Willem Kujawa1,2, Michael Lindner2,7, Ina Koch2,7, Rudolf A Hatz2,7, Juergen Behr2,8, Rocio Sotillo2,6,9, Andrea C Schamberger1,2, Georgios T Stathopoulos10,2,3. 1. Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Helmholtz Center Munich-German Research Center for Environmental Health (HMGU), Munich, Germany. 2. German Center for Lung Research, Giessen, Germany. 3. These authors contributed equally to this work. 4. Institute of Radiation Medicine (IRM), Helmholtz Center Munich-German Research Center for Environmental Health (HMGU), Neuherberg, Germany. 5. Dept of Physiology, Faculty of Medicine, University of Patras, Rio, Greece. 6. Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 7. Center for Thoracic Surgery Munich, Ludwig Maximilian University of Munich and Asklepios Medical Center, Gauting, Germany. 8. Dept of Medicine V, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany. 9. Translational Lung Research Center Heidelberg (TRLC), German Center for Lung Research (DZL), Heidelberg, Germany. 10. Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Helmholtz Center Munich-German Research Center for Environmental Health (HMGU), Munich, Germany stathopoulos@helmholtz-muenchen.de.
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.
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.
Authors: Lisa J Krüger; Julian A F Klein; Frank Tobian; Mary Gaeddert; Federica Lainati; Sarah Klemm; Paul Schnitzler; Ralf Bartenschlager; Berati Cerikan; Christopher J Neufeldt; Olga Nikolai; Andreas K Lindner; Frank P Mockenhaupt; Joachim Seybold; Terry C Jones; Victor M Corman; Nira R Pollock; Britta Knorr; Andreas Welker; Margaretha de Vos; Jilian A Sacks; Claudia M Denkinger Journal: Infection Date: 2021-08-12 Impact factor: 7.455