The Expression of Four Genes as a Prognostic Classifier for Stage I Lung Adenocarcinoma in 12 Independent Cohorts

Background: We previously developed a prognostic classifier using the expression levels of BRCA1, HIF1A, DLC1, and XPO1 that identified stage I lung adenocarcinoma patients with a high risk of relapse. That study evaluated patients in five independent cohorts from various regions of the world. In an attempt to further validate the classifier, we have used a meta-analysis-based approach to study 12 cohorts consisting of 1,069 tumor-node-metastasis stage I lung adenocarcinoma patients from every suitable, publically available dataset. Methods: Cohorts were obtained through a systematic search of public gene expression datasets. These data were used to calculate the risk score using the previously published 4-gene risk model. A fixed effect metaanalysis model was used to generate a pooled estimate for all cohorts. Results: The classifier was associated with prognosis in 10 of the 12 cohorts (P < 0.05). This association was highly consistent regardless of the ethnic diversity or microarray platform. The pooled estimate demonstrated that patients classified as high risk had worse overall survival for all stage I [HR, 2.66; 95% confidence interval (CI), 1.93-3.67; P < 0.0001] patients and in stratified analyses of stage IA (HR, 2.69; 95% CI, 1.66-4.35; P < 0.0001) and stage IB (HR, 2.69; 95% CI, 1.74-4.16; P < 0.0001) patients. Conclusions: The 4-gene classifier provides independent prognostic stratification of stage IA and stage IB patients beyond conventional clinical factors. Impact: Our results suggest that the 4-gene classifier may assist clinicians in decisions about the postoperative management of early-stage lung adenocarcinoma patients. (C) 2014 AACR.