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Updated: May 7, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
A prognostic DNA methylation signature for stage I non-small-cell lung cancer
Juan Sandoval1, Jesus Mendez-Gonzalez, Ernest Nadal
1Juan Sandoval, Jesus Mendez-Gonzalez, F. Javier Carmona, Sergi Sayols, Sebastian Moran, Holger Heyn, Miguel Vizoso, Antonio Gomez, Montse Sanchez-Cespedes, and Manel Esteller, Bellvitge Biomedical Research Institute; Josefina Mora, Hospital de la Santa Creu i Sant Pau; Manel Esteller, University of Barcelona and Institucio Catalana de Recerca i Estudis Avançats, Barcelona; Miquel Taron and Rafael Rosell, Catalan Institute of Oncology, Badalona, Catalonia; Marina Pollan, Instituto de Salud Carlos III, Madrid; Maria J. Pajares and Luis M. Montuenga, University of Navarra; Wenceslao Torre, Clínica University de Navarra, Pamplona, Spain; Ernest Nadal, Guoan Chen, and David G. Beer, University of Michigan Medical School, Ann Arbor, MI; Yassen Assenov and Fabian Müller, Max Planck Institute, Saarbrücken, Germany; Christoph Bock, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Lucia A. Muscarella, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Triantafillos Liloglou, Michael Davies, and John K. Field, The University of Liverpool Cancer Research Centre, Liverpool, United Kingdom; Elisabeth Brambilla, Centre Hospitalier Universitaire A Michallon, Grenoble, France; Luca Roz, IRCCS Foundation National Cancer Institute, Milan; Marco Lo Iacono and Giorgio V. Scagliotti, University of Torino, Orbassano (Torino), Italy.
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.
