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 journalArticlepeer-review


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. 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. 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). 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)4140-4147
Number of pages8
JournalJournal of Clinical Oncology
Issue number32
Publication statusPublished - Nov 10 2013

ASJC Scopus subject areas

  • Medicine(all)


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