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

Authors

• AI Robles
• E Arai
• EA Mathe
• H Okayama
• AJ Schetter
• D Petersen
• ED Bowman
• R Noro
• JA Welsh
• DC Edelman
• HS Stevenson
• Y Wang
• A Haugen
• PS Meltzer
• J Yokota
• Y Kanai
• CC Harris

Abstract

Up to 30% of Stage I lung cancer patients will succumb to metastatic disease within 5 years of curative surgery. Therefore, there is a need for biomarkers that provide information about likelihood of recurrence. We analyzed the lung cancer epigenome and discovered methylation biomarkers that improve existing protein-coding gene and microRNA expression prognostic classifiers. We retrospectively analyzed tissue samples from patients with early stage lung cancer by genome-wide screening of DNA methylation followed by pyrosequencing. The prognostic significance of HOXA9 promoter methylation alone and in combination with four protein-coding gene (XPO1, BRCA1, HIF1α, DLC1), and miR-21 expression was assessed by Cox regression and Kaplan-Meier in two independently collected cohorts of Stage I lung adenocarcinoma. Promoters of genes marked by Polycomb in Embryonic Stem Cells were methylated de novo in tumors and identified patients with poor prognosis. 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 Stage IA and IB. Protein-coding gene, miR-21 and HOXA9 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 naïve, Stage I patients (HR, 10.2; P = 3x10-5). 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.

Scientific Focus Area: Cancer Biology

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