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

+Author Affiliations

¹Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
²Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
³Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer, Barcelona, Spain.
⁴Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.

↵*Corresponding Author:
Curtis C. Harris, Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, 37 Convent Dr. MSC4258, Building 37, Room 3068A, Bethesda, MD 20892-4258. Phone: 301-496-2048; Fax: 301-496-0497; E-mail: Curtis_Harris@nih.gov

H. Okayama and A.J. Schetter contributed equally to this article.

Abstract

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 meta-analysis 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. Cancer Epidemiol Biomarkers Prev; 1–11. ©2014 AACR.