Purpose: To explore the utility of cell-free DNA (cfDNA) from bronchoalveolar lavage fluids (BALF) using next generation sequencing (NGS) in differentiating malignant tumors from benign solitary pulmonary nodule (SPN).Methods: Between January 1st 2019 and January 1st 2021, 40 subjects undergoing computed tomography (CT) examination who were diagnosed with SPN, were prospectively enrolled at Zhangzhou Affiliated Hospital of Fujian Medical University (Zhangzhou, Fujian, China). And pathological

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... agnosis were finally confirmed from tissue specimens obtained by surgical resection. For each patient, the mutations of gene were analysed using NGS in both extraction of cfDNA isolated from BALF and tissue. Results: Of 40 patients, 55% of them were diagnosed with lung adenocarcinoma, 20% with benign nodules, and 10% with small cell carcinoma. And patients with squamous carcinoma, adenosquamous carcinoma or large cell neuroendocrine carcinoma account for 5%, respectively. And 62.5% of malignant SPN (10/16) had at least one alteration. The most common alterations were TP53 (31.25%), followed by EGFR (18.75%), KRAS (12.5%), PIK3CA (6.25%), ERBB2 (6.25%), ALK (6.25%) and ROS1 (6.25%). Besides, there are some differences shown in the heatmap of gene mutation in the histologic sample. And there was a colse correlation between the mutations found in the tissue and BALF. For all 40 patients, the sensitivity, specificity, and concordance of BALF in predicting malignant nodules were 68.8%, 100%, and 75%, respectively. Conclusions: By NGS, tumor-specific mutations of cfDNA from BALF may be benefical to predicting malignant SPN, which may be taken into consideration for personalized cancer diagnosis.