Tumor-based gene expression biomarkers to predict survival following curative intent resection for stage I lung adenocarcinoma

Alisson Clemenceau,Yohan Bossé,Catherine Labbé,Paula A Ugalde,Michel Laviolette,Philippe Joubert,Cyndi Henry,Nathalie Gaudreault,Alfons Navarro

doi:10.1371/journal.pone.0207513

Alisson Clemenceau, Yohan Bossé + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0207513

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Abstract

BackgroundPrognostic biomarkers are needed in clinical setting to predict outcome after resection for early-stage lung adenocarcinoma. The goal of this study is to validate tumor-based single-gene expression biomarkers with demonstrated prognostic value in order to move them along the clinical translation pipeline.MethodsPrognostic genes were selected from the literature and the best candidates measured by quantitative real-time polymerase chain reaction (qPCR) in tumors of 233 patients with stage I adenocarcinoma. Significant prognostic genes were then validated in an independent set of 210 patients matching the first set in terms of histology, stage, and clinical data.ResultsEleven genes with demonstrated prognostic value were selected from the literature. Complementary analyses in public databases and our own microarray dataset led to the investigation of six genes associated with good (BTG2, SELENBP1 and NFIB) or poor outcome (RRM1, EZH2 and FOXM1). In the first set of patients, EZH2 and RRM1 were significantly associated with better survival on top of age, sex and pathological stage (EZH2 p = 3.2e-02, RRM1 p = 5.9e-04). The prognostic values of EZH2 and RRM1 were not replicated in the second set of patients. A trend was observed for both genes in the joint analyses (n = 443) with higher expression associated with worse outcome.ConclusionAdenocarcinoma-specific mRNA expression levels of EZH2 and RRM1 are associated with poor post-surgical survival in the first set of patients, but not replicated in a clinically and pathologically matched independent validation set. This study highlights challenges associated with clinical translation of prognostic biomarkers.

Highlights

Surgery remains the first line of treatment for operable and resectable stage I pulmonary adenocarcinoma
The prognostic values of EZH2 and RRM1 were not replicated in the second set of patients
Adenocarcinoma-specific messenger ribonucleic acid (mRNA) expression levels of EZH2 and RRM1 are associated with poor post-surgical survival in the first set of patients, but not replicated in a clinically and pathologically matched independent validation set

Summary

Introduction

Surgery remains the first line of treatment for operable and resectable stage I pulmonary adenocarcinoma This histological subtype and stage represents the largest proportion of patients undergoing surgical intervention. There is an urgent need to identify postoperative stage I adenocarcinoma lung cancer patients at high risk of recurrence in order to guide adjuvant therapy. No gene or signature has been widely implemented in lung cancer clinical setting. We attempted to validate genes with demonstrated prognostic value in two independent sets of patients with early-stage lung adenocarcinoma. Prognostic biomarkers are needed in clinical setting to predict outcome after resection for early-stage lung adenocarcinoma. The goal of this study is to validate tumor-based singlegene expression biomarkers with demonstrated prognostic value in order to move them along the clinical translation pipeline

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