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. 2023 Jan 20;15(4):921–929. doi: 10.1016/j.jcmgh.2023.01.001

Figure 2.

Figure 2

Cell-free vh-DNA from HBV integration sites is a new biomarker to monitor postresection residual disease or to track clonal hyperplasia to HCC. (A) HCC-specific junction fragments in detecting postresection residual disease and recurrence. After surgical resection, HCC (red tumor in the liver) was removed (dotted circle), and its corresponding circulating vh-chimera DNA (chimera DNA with red for virus sequence and blue for human sequence) was cleared from circulation. If there is residual circulating vh-chimera DNA after resection, intrahepatic HCC is not completely removed and will likely recur (red tumor in the liver). In contrast, for those without residual vh-chimera DNA from the original HCC, recurrence HCC likely arises from a new origin (de novo HCC, green tumor in the liver). Detection of de novo HCC may require Cap-seq to analyze the circulating cell-free DNA for vh-chimeras (chimera DNA with green for the virus sequence and blue for the human sequence). (B) Progression from chronic hepatitis B and clonal hyperplasia to HCC is depicted with circulating vh-chimera DNA. As cells in HCC-prone clonal hyperplasia contain HBV integrations (cells with different colors in the liver), their specific junction fragments are released into the circulation as virus‒host chimera DNA (human sequence in blue and virus sequences from individual clones in red, green, purple, or yellow). The amount of cell-free vh-DNA is positively associated with the size of HBV integration (+) clonal hepatocytes or HCC (indicated by the height of vh-DNA). The threshold of Cap-seq and droplet digital PCR for detecting vh-chimera DNA from HCC is indicated by a straight lines. If the sensitivity and specificity of next-generation Cap-seq can be improved, it might be used to detect the low level of vh-chimera DNA from clonal hyperplasia with indeterminate potential (CHIP). This will be applied to CHIP to HCC in the future without prior knowledge of HBV integration sites. (C) Inverse course of circulating HBV DNA/HBsAg versus virus‒host chimera DNA levels in the progression from chronic hepatitis B to HCC. The level of HBV DNA or HBsAg usually declines, but that of circulating virus‒host chimera DNA increases synchronously with the development of HCC. Refer to reference 64.