title: An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: *Laboratory of Human Carcinogenesis, NCI-CCR, National Institutes of Health, Bethesda, Maryland; †Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan; ‡Genetics Branch, NCI-CCR, National Institutes of Health, Bethesda, Maryland; §Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; ‖Department of Chemical and Biological Working Environment, National Institute of Occupational Health, Oslo, Norway; and ¶Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona (Barcelona), Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Robles
authors.forename: Eri
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authors.lastname: Arai
authors.forename: Ewy A
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authors.lastname: Mathé
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Okayama
authors.forename: Aaron J
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authors.lastname: Schetter
authors.forename: Derek
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authors.lastname: Brown
authors.forename: David
authors.initials: D
authors.lastname: Petersen
authors.forename: Elise D
authors.initials: ED
authors.lastname: Bowman
authors.forename: Rintaro
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authors.lastname: Noro
authors.forename: Judith A
authors.initials: JA
authors.lastname: Welsh
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Edelman
authors.forename: Holly S
authors.initials: HS
authors.lastname: Stevenson
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wang
authors.forename: Naoto
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authors.lastname: Tsuchiya
authors.forename: Takashi
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authors.lastname: Kohno
authors.forename: Vidar
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authors.lastname: Skaug
authors.forename: Steen
authors.initials: S
authors.lastname: Mollerup
authors.forename: Aage
authors.initials: A
authors.lastname: Haugen
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D057285:Precision Medicine; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D012333:RNA, Messenger