A prognostic DNA methylation signature for stage I non-small-cell lung cancer

Juan Sandoval, Jesus Mendez-Gonzalez, Ernest Nadal, Guoan Chen, F Javier Carmona, Sergi Sayols, Sebastian Moran, Holger Heyn, Miguel Vizoso, Antonio Gomez, Montse Sanchez-Cespedes, Yassen Assenov, Fabian Müller, Christoph Bock, Miquel Taron, Josefina Mora, Lucia A Muscarella, Triantafillos Liloglou, Michael Davies, Marina PollanMaria J Pajares, Wenceslao Torre, Luis M Montuenga, Elisabeth Brambilla, John K Field, Luca Roz, Marco Lo Iacono, Giorgio V Scagliotti, Rafael Rosell, David G Beer, Manel Esteller

Research output: Contribution to journalArticle (journal)peer-review

231 Citations (Scopus)


PURPOSE: Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.

PATIENTS AND METHODS: A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.

RESULTS: Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).

CONCLUSION: The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.

Original languageEnglish
Pages (from-to)4140-7
Number of pages8
JournalJournal of Clinical Oncology
Issue number32
Publication statusPublished - 10 Nov 2013


  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor/genetics
  • Carcinoma, Non-Small-Cell Lung/genetics
  • Cluster Analysis
  • CpG Islands/genetics
  • DNA Methylation/genetics
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms/genetics
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Proportional Hazards Models
  • Transcriptome/genetics


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