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. 2015 Jul;10(7):1037-48.
doi: 10.1097/JTO.0000000000000560.

An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers

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Free PMC article

An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers

Ana I Robles et al. J Thorac Oncol. .
Free PMC article

Abstract

Introduction: Up to 30% stage I lung cancer patients suffer recurrence within 5 years of curative surgery. We sought to improve existing protein-coding gene and microRNA expression prognostic classifiers by incorporating epigenetic biomarkers.

Methods: Genome-wide screening of DNA methylation and pyrosequencing analysis of HOXA9 promoter methylation were performed in two independently collected cohorts of stage I lung adenocarcinoma. The prognostic value of HOXA9 promoter methylation alone and in combination with mRNA and miRNA biomarkers was assessed by Cox regression and Kaplan-Meier survival analysis in both cohorts.

Results: Promoters of genes marked by polycomb in embryonic stem cells were methylated de novo in tumors and identified patients with poor prognosis. The HOXA9 locus was methylated de novo in stage I tumors (p < 0.0005). High HOXA9 promoter methylation was associated with worse cancer-specific survival (hazard ratio [HR], 2.6; p = 0.02) and recurrence-free survival (HR, 3.0; p = 0.01), and identified high-risk patients in stratified analysis of stages IA and IB. Four protein-coding gene (XPO1, BRCA1, HIF1α, and DLC1), miR-21 expression, and HOXA9 promoter methylation were each independently associated with outcome (HR, 2.8; p = 0.002; HR, 2.3; p = 0.01; and HR, 2.4; p = 0.005, respectively), and when combined, identified high-risk, therapy naive, stage I patients (HR, 10.2; p = 3 × 10). All associations were confirmed in two independently collected cohorts.

Conclusion: A prognostic classifier comprising three types of genomic and epigenomic data may help guide the postoperative management of stage I lung cancer patients at high risk of recurrence.

Figures

Fig. 1
Fig. 1
Methylation of genes marked by H3K27me3 in Embryonic Stem Cells (ESC) is associated with clinical outcome. Hierarchical clustering based on hypermethylated CpGs of genes marked by H3K27me3 in ESC in the NCI (A) and Japan (C) microarray cohorts. Each column represents an individual patient and each row an individual CpG probe. Patients in the high methylation clusters had shorter cancer-specific (B) or relapse-free (D) survival, respectively, in Kaplan-Meier survival analysis.
Fig. 2
Fig. 2
Kaplan-Meier analysis of HOXA9 promoter methylation in Stage I lung ADC. HOXA9 methylation values were dichotomized based on ≥ 40%/< 40% mean methylation in pyrosequencing analysis. The associations were evaluated in two independent cohorts, including the combined NCI/Norway cohort (left panels) and the Japan cohort (right panels). Shown are the analysis of Stage I (A), and the subgroup analysis of Stage IA (B) and Stage IB (C). P values were calculated by log-rank test.
Fig. 3
Fig. 3
Kaplan-Meier analysis of a combined prognostic biomarker in Stage I lung ADC. Patients in the combined NCI/Norway cohort (left panels) and the Japan cohort (right panels) were categorized according to the combined number of high values for HOXA9 methylation, miR-21 and 4-protein-coding gene signature. An increasing combined score conferred greater risk for poor outcome in Stage I (A), and within subgroup analysis of Stage IA (B) and Stage IB (C). P values calculated by log-rank test.

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