Association of FOSB exon 4 unmethylation with poor prognosis in patients with late‑stage non‑small cell lung cancer.

Alterations in DNA methylation have a central role in the development and outcome of most human malignancies. Non-small cell lung cancer (NSCLC), the most common lung cancer, leads to the largest number of cancer-related deaths worldwide. FBJ murine osteosarcoma viral oncogene homolog B (FOSB) is a key component of the activator protein-1 transcription factor and regulates gene networks associated within oncogenic transformation. The role of FOSB in the development of NSCLC is still elusive. Therefore, the methylation status of the FOSB gene was investigated in NSCLC and its clinical significance in NSCLC progression was evaluated. The methylation status of the promoter and exon 4 regions of the FOSB gene were analyzed in 176 NSCLC specimens by bisulfite pyrosequencing and the association between FOSB methylation status and patient survival was investigated. Compared to adjacent non-malignant tissues, FOSB promoter exhibited exclusive unmethylation in all malignant tissues and the exon 4 region was found unmethylated in 18 (10.2% of the total) tumor samples. Exon 4 unmethylation was associated with downregulation of its mRNA and tended to occur in patients with lymph node metastasis. Univariate and multivariate analyses revealed that exon 4 unmethylation was significantly associated with unfavorable overall survival in patients with stage II-IIIA NSCLC (log-rank P=0.05, adjusted hazard ratio=2.43, 95% confidence interval=1.04-5.68, P=0.04). FOSB was identified as a novel gene with tumor-specific gene body unmethylation in NSCLC and a novel predictive biomarker for NSCLC prognosis. Moreover, the present results indicated that FOSB may have a tumor suppressor function in the progression of NSCLC.