Genomic characterization of early-stage hepatocellular carcinoma patients with Hepatitis B using circulating tumor DNA

Hepatocellular carcinoma (HCC) is a leading cause of mortality, with Hepatitis B virus (HBV) infection as a dominant etiology worldwide. Effective early detection strategies may facilitate curative therapies and improve survival. We investigated genomic aberrations in circulating tumor DNA (ctDNA) as potential diagnostic markers of HCC in HBV-infected patients. We identified early stage (BCLC 0-A) HCC cases ( n  = 21) and patients without HCC ( n  = 14) from a cohort of Asian patients with HBV, undergoing surveillance between 2013 and 2017. Circulating cell-free DNA was isolated from blood samples, and assayed by next-generation sequencing of 23 genes implicated in HCC pathogenesis. Somatic mutations were identified using a computational pipeline. Using area under the curve (AUC) in receiver operating characteristic (ROC) analysis, we evaluated gene alterations and clinical factors in an exploratory early HCC detection model. Mutant ARID1A, CTNNB1, TP53 genes were increased in HCC cases vs. non-HCC patients (85.7% vs 42.9%, P  = 0.011; 42.9% vs 0%, P  = 0.005; 100% vs 71.4%, P  = 0.019, respectively). Using these three genes, AUC for discriminating HCC from non-HCC patients was 0.844 (95% confidence interval [CI]: 0.7317–0.9553). When combining these genes with clinical factors in an exploratory early HCC detection model, AUC increased from 0.7415 (using clinical factors alone) to 0.9354 ( P  = 0.041). Genomic aberrations in ctDNA were more prevalent in HBV-infected HCC patients compared with patients without HCC. Combining these alterations with clinical factors may identify HCC in HBV-infected patients at an early stage. These findings warrant validation in future studies.