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Single-Cell Analysis of Viral Integration in Multifocal Hepatocellular Carcinoma During Occult Hepatitis B Infection
Qian Chen*
GI, Tongji Hospital, Wuhan, China
BACKGROUND
The hepatitis B virus (HBV) [DE1] is a major causative agent of hepatocellular carcinoma (HCC). Integration of the virus DNA into the host's genome leads to a persistent occult infection that can be sufficient to induce hepatocyte transformation. Patients with HCC frequently develop multiple anatomically distinct liver tumors at an early stage, which severely limits the benefit of surgical therapy. To identify the viral integration events that could be responsible for the presence of the multifocal tumors, we studied the pattern of HBV DNA integration in an HCC patient with an occult HBV infection.
METHODS
We combined advanced liquid-phase hybridization techniques with single-cell sequencing to analyze the virus integration sites within individual cells. The pattern of HBV integration was used as a genetic marker to determine the clonal evolution of HCC in both the primary tumor and the liver metastases.
RESULTS
Despite a lack of detectable HBV DNA in the patient's serum, we determined numerous virus integration sites in the liver tissue. Two frequent breakpoints within the HBV genome were identified in the precore/core region, and these preferentially affected two host genes, located at the intergenic region of MED30-EXT1 on chromosome 8 and at the intragenic region of CSMD2 on chromosome 1.
CONCLUSIONS
Our work indicates that the integration of HBV DNA sequences into hepatocytes may take place early and systemically during the development of multiple tumors in the liver. Furthermore, the sites of oncogenic viral integration are not random and occur in genes that may have important roles in carcinogenesis and in HCC metastasis.
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