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Purpose: Intratumoral hepatitis B virus (HBV) integrations and mutations are related to hepatocellular carcinoma (HCC) progression. Circulating cell-free DNA (cfDNA) has shown itself as a powerful noninvasive biomarker for cancer. However, the HBV integration and mutation landscape on cfDNA remains unclear. Experimental Design: A cSMART (Circulating Single-Molecule Amplification and Resequencing Technology)-based method (SIM) was developed to simultaneously investigate HBV integration and mutation landscapes on cfDNA with HBV-specific primers covering the whole HBV genome. Patients with HCC (n = 481) and liver cirrhosis (LC; n = 517) were recruited in the study. Results: A total of 6,861 integration breakpoints including TERT and KMT2B were discovered in HCC cfDNA, more than in LC. The concentration of circulating tumor DNA (ctDNA) was positively correlated with the detection rate of these integration hotspots and total HBV integration events in cfDNA. To track the origin of HBV integrations in cfDNA, whole-genome sequencing (WGS) was performed on their paired tumor tissues. The paired comparison of WGS data from tumor tissues and SIM data from cfDNA confirmed most recurrent integration events in cfDNA originated from tumor tissue. The mutational landscape across the whole HBV genome was first generated for both HBV genotype C and B. A region from nt1100 to nt1500 containing multiple HCC risk mutation sites (OR > 1) was identified as a potential HCC-related mutational hot zone. Conclusions: Our study provides an in-depth delineation of HBV integration/mutation landscapes at cfDNA level and did a comparative analysis with their paired tissues. These findings shed light on the possibilities of noninvasive detection of virus insertion/mutation.

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Aim In the present study, we purposed to determine serum chitinase 3‐like 1 (CHI3L1) expression characteristics in chronic liver diseases monoinfected with hepatitis B virus and analyze its diagnostic value in liver fibrosis. Methods A total of 467 chronic hepatitis B (CHB) patients, 312 liver cirrhosis (LC) patients, and 104 hepatocellular carcinoma (HCC) patients at our institution were enrolled, and clinical indicators were analyzed. Results Our data have shown that the expression level of serum CHI3L1 was steadily increased from CHB to LC to HCC (P < .001). Serum CHI3L1 expression levels were positively associated with liver stiffness measurement (LSM), fibrosis‐4 (FIB‐4) index, aspartate aminotransferase‐to‐platelet ratio index (APRI), and HCC stage. The receiver operating characteristic (ROC) curve proved that serum CHI3L1 was superior to other noninvasive methods (LSM, FIB‐4, and APRI) with an area under the ROC curve (AUC) of 0.97 in diagnosing significant fibrosis. Conclusions Serum CHI3L1 harbors significant clinical value in chronic liver diseases infected with hepatitis B virus, especially in the diagnosis of fibrosis.