Abstract
PurposeWe had previously developed highly sensitive DNA methylation detection to diagnose lung cancer in patients with pulmonary nodules. To validate this approach and determine clinical utility in Chinese patients with indeterminate pulmonary nodules, we assessed the diagnostic accuracy for early stage lung cancer in plasma samples.Experimental designPatients with CT-detected small lung nodules (diameter ≤ 3.0 cm) were included. Cases (n = 163) had staged IA or IB non-small cell lung cancer (NSCLC), while controls (n = 83) had non-cancerous lesions. Promoter methylation of eight lung cancer-specific genes (CDO1, TAC1, SOX17, HOXA7, HOXA9, GATA4, GATA5, and PAX5) was detected using nanoparticle-based DNA extraction (MOB) followed by qMSP.ResultsMethylation detection for CDO1, TAC1, SOX17, and HOXA7 in plasma was significantly higher in cases compared with the benign group (p < 0.001). The sensitivity and specificity for lung cancer diagnosis using individual gene was 41–69% and 49–82%. A three-gene combination of the best individual genes has sensitivity and specificity of 90% and 71%, with area under the receiver operating curve (AUC) of 0.88, (95% CI 0.84–0.93). Furthermore, three-gene combinations detected even the smallest lung nodules, with the combination of CDO1, SOX17, and HOXA7 having the overall best performance, while the combination of CDO1, TAC1, and SOX17 was best in tumor sizes less than 1.0 cm.ConclusionsUsing modified MOB-qMSP, high sensitivity and specificity, for the detection of circulating tumor DNA was obtained for early stage NSCLC. This strategy has great potential to identify patients at high risk and improve the diagnosis of lung cancer at an earlier stage.Graphical
Highlights
Lung cancer remains the leading cause of cancer-related death in the world [1, 2]
Methylation detection for CDO1, TAC1, SOX17, and HOXA7 in plasma was significantly higher in cases compared with the benign group (p < 0.001)
A three-gene combination of the best individual genes has sensitivity and specificity of 90% and 71%, with area under the receiver operating curve (AUC) of 0.88
Summary
DNA methylation [11, 12], circulating tumor cells [10], and cancer-specific auto-antibodies [13], that could improve the diagnostic accuracy for detection of early stage of lung cancer. Circulating tumor DNA (ctDNA), which refers to DNA released from lysed or apoptotic tumor cells and circulating freely in blood, is a promising approach for the detection of very early stage of lung cancer [14, 15]. Methylation of cytosine in CpG islands silences hundreds of genes that are involved in the initiation and progression of lung cancer. Several studies have reported cancer-specific DNA methylation changes detectable in plasma, sputum, saliva, and pleural effusions from the patients with lung cancer [9, 11, 17]
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