As a prospective, multi-center study, GUIDER will recruit 400 liver nodules participants from different provinces and regions across China. Except for cfDNA signatures, serum biomarkers, histopathological biopsy and enhanced MRI will also be performed. The sensitivity and specificity of the cfDNA signature based-model in liver nodules diagnosing will be evaluated.

Patients with liver nodules will be recruited for 1 year. Peripheral blood samples of all participants will be collected after being informed about the study and potential risks. CfDNA extraction, library construction, and whole genome sequencing will be performed. A machine learning method will be implemented for cfDNA signatures-based model construction at the end of the study. Sensitivity and specificity will be used to evaluate the performance of cfDNA signatures-based model in liver nodules diagnosis.

Inclusion Criteria:

• Eighteen years or elder；
• Participants underwent enhanced MRI for the evaluation of liver nodules ≤5 cm；
• Participants whose platelet count ≥ 50×109/L, prothrombin activity (PTA) ≥ 60%；
• Participants who are willing and able to perform hepatectomy or tissure biopsy.

Exclusion Criteria:

• Participants with different enhancement mode liver nodules that detected by enhanced MRI and without CEUS confirmation；
• Diagnosis of malignant tumors before recruitment；
• Anti-tumor therapy before recruitment ；
• HIV infection；
• Pregnancy；
• Allogenic blood transfusion or cell therapy within 14 days before peripheral blood samples collection;
• Participants with hepatic encephalopathy, hemangioma, ascites, gastrointestinal bleeding, jaundice, liver failure, congestive heart failure, or any other serious diseases that causing organ damage.
• Participants with any other factors that may leading to termination of the study.

Four hundreds eligible participants will be recruited from medical centers and assigned into three groups, including participants with malignant or benign liver nodules，and participants with uncertain liver nodules.