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Huan Wang,1,* Teng Zhang,2,* Liqun Li,3 Feina Lin,1 Xujing Yuan,1 Jing Wang,1 Jiadong Xu,1 Haijun Xu,4 Feng Zhou,4 Weifeng Luo,2 Zhijun Chen1 1Department of Cardiothoracic Surgery, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, People’s Republic of China; 2Shanghai R & S Biotechnology Co., Ltd, Shanghai, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, People’s Republic of China; 4Lincheng Street Community Health Service Center, Zhoushan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhijun Chen, Email zschenzhijun@126.comBackground: Low-Dose Computed Tomography (LDCT) is commonly used to detect pulmonary nodules; however, it may also contribute to overdiagnosis. DNA methylation shows promise as an approach to discriminate early-stage lung cancer (LC) patients from individuals with benign nodules (hereafter referred to as benign pulmonary nodule group) and healthy individuals.Methods: This study investigated the performance of DNA methylation in three genes (TAC1, SOX17, and RASSF1A) in plasma-derived cell-free DNA (cfDNA) for discriminating LC patients from benign and healthy individuals (collectively referred to as benign/healthy individuals). We enrolled 149 LC patients (96 with early-stage [stage IA] and 53 with advanced-stage [non-IA]), 54 benign pulmonary nodule group, and 75 healthy individuals.Results: Methylation-positive rates for all three genes were significantly higher in LC patients compared to benign/healthy individuals. A combined three-gene model based on the ΔCt values of the three genes demonstrated robust diagnostic performance, achieving a sensitivity of 97.7%, specificity of 96.6%, and an area under the curve (AUC) of 0.99 for discriminating LC patients from benign/healthy individuals. Furthermore, another combined three-gene model based on the ΔCt values of the same genes showed high diagnostic performance for discriminating IA-stage LC patients from benign/healthy individuals, with a sensitivity of 96.9%, specificity of 88.54%, and AUC of 0.95.Conclusion: This study highlights the robust diagnostic value of a combined three-gene (TAC1, SOX17, and RASSF1A) methylation model for detecting LC, including early-stage disease, offering high sensitivity and specificity.Keywords: DNA methylation, diagnosis, lung cancer, early-stage