Efficacy of ctDNA methylation combined with traditional detection modality to detect liver cancer among high-risk patients: A multicenter diagnostic trial.

Objective: Circulating tumor DNA (ctDNA) and alpha-fetoprotein (AFP) plus ultrasound (US) have been considered to have high diagnostic accuracy for cancer detection, however, the efficacy of ctDNA methylation combined with the traditional detection modality of liver cancer has not been tested in a Chinese independent cohort. Methods: The high-risk individuals aged between 35 and 70 years who were diagnosed with liver cirrhosis or had moderate and severe fatty liver were eligible for inclusion. All participants were invited to receive a traditional examination [referring to AFP plus US], and ctDNA methylation, respectively. The sensitivity and specificity of different diagnostic tools were calculated. The logistic regression model was applied to estimate the area under the curve (AUC), which was further validated by 10-fold internal cross-validation. Results: A total of 1,205 individuals were recruited in our study, and 39 participants were diagnosed with liver cancer. The sensitivity of AFP, US, US plus AFP, and the combination of US, AFP, and ctDNA methylation was 33.33%, 56.41%, 66.67%, and 87.18%, respectively. The corresponding specificity of AFP, US, US plus AFP, and the combination of all modalities was 98.20%, 99.31%, 97.68%, and 97.68%, respectively. The AUCs of AFP, US, US plus AFP, and the combination of AFP, US, and ctDNA methylation were 65.77%, 77.86%, 82.18%, and 92.43%, respectively. The internally validated AUCs of AFP, US, US plus AFP, and the combination of AFP, US, and ctDNA methylation were 67.57%, 83.26%, 86.54%, and 93.35%, respectively. Conclusions: The ctDNA methylation is a good complementary to AFP and US for the detection of liver cancer.