Thoracic: Lung Cancer| Volume 165, ISSUE 4, P1554-1564.e1, April 2023

A unique gene signature predicting recurrence-free survival in stage IA lung adenocarcinoma

Published:September 23, 2022DOI:



      Resected stage IA lung adenocarcinoma has a reported 5-year recurrence-free survival of 63% to 81%. A unique gene signature stratifying patients with early-stage lung adenocarcinoma as having a high or low risk of recurrence would be valuable.


      Gene Expression Omnibus datasets combining European and North American patients with lung adenocarcinoma (n = 684) were filtered for stage IA (n = 105) to develop a robust signature for recurrence. A univariate Cox proportional hazard regression model was used to assess the associations of gene expression with recurrence-free survival and overall survival. Leveraging a bootstrap approach of these identified upregulated genes allowed construction of a model that was evaluated by area under the receiver operating characteristics. The optimal signature has robust signature for recurrence calculated via a linear combination of expression of selected genes weighted by the corresponding Cox regression-derived coefficients. Log-rank analysis calculated recurrence-free survival and overall survival. Results were validated using the lung adenocarcinoma The Cancer Genome Atlas transcriptomic next-generation sequencing-based dataset.


      Rigorous bioinformatic analysis identified a signature of 4 genes: kinetochore-localized astrin binding protein, platelet-activating factor acetylhydrolase 1B3, macrophage inhibitory factor, and checkpoint kinase 1. Kaplan–Meier analysis of stage IA lung adenocarcinoma with this signature resulted in 5-year recurrence-free survival for low risk of 90% compared with 53% for high risk (hazard ratio, 6.55, 95% confidence interval, 2.65-16.18, P < .001), confirming the robustness of the gene signature with its clinical significance. Validation of the signature using The Cancer Genome Atlas dataset resulted in an area under the curve of 0.797 and 5-year recurrence-free survival for low- and high-risk patients with stage IA being 91% and 67%, respectively (hazard ratio, 3.44, 95% confidence interval, 1.16-10.23, P = .044).


      This 4-gene signature stratifies European and North American patients with pathologically confirmed stage IA lung adenocarcinoma into low- and high-risk groups for overall survival and, more important, recurrence-free survival.

      Graphical abstract

      Key Words

      Abbreviations and Acronyms:

      AUC (area under the curve), CHEK1 (checkpoint kinase 1), CI (confidence interval), DEG (differential expression gene), EGFR (endothelial growth factor receptor), GEO (Gene Expression Omnibus), HR (hazard ratio), KNSTRN (kinetochore-localized astrin binding protein), LUAD (lung adenocarcinoma), MIF (macrophage inhibitory factor), NSCLC (non–small cell lung cancer), OS (overall survival), PAFAH1B3 (platelet-activating factor acetylhydrolase 1B3), RFS (recurrence-free survival), TCGA (The Cancer Genome Atlas)
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