Abstract
Objective
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.
Methods
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.
Results
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).
Conclusions
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
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)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: September 23, 2022
Accepted:
September 10,
2022
Received in revised form:
August 23,
2022
Received:
June 6,
2022
Footnotes
This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) (S.R.C.), NIH Intramural Grant (ZIA BC 011115; D.S.S.), and the Stephen J. Solarz Memorial Fund, Foundation for the NIH.
The Institutional Review Board of the NIH did not require approval of this study because all datasets are publicly available for download and analysis (45 CFR 144 46.101(b)).
Drs Carr and Wang contributed equally to this article.
Identification
Copyright
Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery
