Promoter methylation status of is associated with decreased overall survival and TNM status in patients with early stage non-small cell lung cancer (NSCLC).

BACKGROUND

Lung cancer is the leading cause of cancer-related death worldwide, with 5-year overall survival less than 15%. Therefore, it is essential to find biomarkers for early detection and prognosis. Aberrant DNA methylation is a common feature of human cancers and its utility is already recognized in cancer management. The aim of this study was to explore the diagnostic and prognostic value of the promoter methylation status of the and genes, key adaptor molecules in the activation of the innate immune response and apoptosis pathways.

METHODS

A total of 50 non-small cell lung cancer (NSCLC) patients were enrolled in the study. Methylation of bisulphite converted DNA was quantified by pyrosequencing in fresh frozen malignant tissues and adjacent non-malignant tissues. Associations between methylation and lung function, tumor grade and overall survival were evaluated using receiver-operating characteristics (ROC) analysis and statistical tests of hypothesis.

RESULTS

Methylation level of tested genes is generally low but significantly decreased in tumor tissues (, P<0.0001; , P<0.0002), which correlates with increased protein expression. Three CpG sites were identified as promising diagnostic marker candidates; CpG11 (-63 position) in and CpG1 (-253 position) and 2 (-265 position) in . The association study showed that the methylation status of the CpG4 site (-34 position) in malignant and non-malignant tissues is associated with the overall survival (P=0.019) and the methylation status of CpG8 site (-92 position) is associated with TNM-stage (P=0.011).

CONCLUSIONS

The methylation status of the and promoters are promising prognostic biomarker candidates. However, presented results should be considered as a preliminary and should be confirmed on the larger number of the samples.