A Prognostic DNA Methylation Signature for Stage I Non-Small-Cell Lung Cancer

作者：Sandoval Juan; Mendez Gonzalez Jesus; Nadal Ernest; Chen Guoan; Carmona F Javier; Sayols Sergi; Moran Sebastian; Heyn Holger; Vizoso Miguel; Gomez Antonio; Sanchez Cespedes Montse; Assenov Yassen; Mueller Fabian; Bock Christoph; Taron Miquel; Mora Josefina; Muscarella Lucia A; Liloglou Triantafillos; Davies Michael; Pollan Marina; Pajares Maria J; Torre Wenceslao; Montuenga Luis M; Brambilla Elisabeth; Field John K; Roz Luca; Lo Iacono Marco

来源：Journal of Clinical Oncology, 2013, 31(32): 4140-+.

DOI：10.1200/JCO.2012.48.5516

Purpose %26lt;br%26gt;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. %26lt;br%26gt;Patients and Methods %26lt;br%26gt;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. %26lt;br%26gt;Results %26lt;br%26gt;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). %26lt;br%26gt;Conclusion %26lt;br%26gt;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.

• 出版日期2013-11-10