TY - JOUR
T1 - Viral integration drives multifocal HCC during the occult HBV infection
AU - Chen, Xiao-Ping
AU - Long, Xin
AU - Jia, Wen-Long
AU - Wu, Han-Jie
AU - Zhao, Jing
AU - Liang, Hui-Fang
AU - Laurence, Arian
AU - Zhu, Jun
AU - Dong, Dong
AU - Chen, Yan
AU - Lin, Long
AU - Xia, Yu-Dong
AU - Li, Wei-Yang
AU - Li, Gui-Bo
AU - Zhao, Zhi-Kun
AU - Wu, Kui
AU - Hou, Yong
AU - Yu, Jing-Jing
AU - Xiao, Wei
AU - Wang, Guo-Ping
AU - Zhu, Peng-Cheng
AU - Chen, Wei
AU - Bai, Ming-Zhou
AU - Jian, Yi-Xing
AU - Kristiansen, Karsten
AU - Chen, Qian
PY - 2019
Y1 - 2019
N2 - Background & Aims: Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We studied the mechanism of life-long Integration of virus DNA into OBI host's genome, of which may induce hepatocyte transformation. Methods: We applied HBV capture sequencing on single cells from an OBI patient who, developed multiple HCC tumors and underwent liver resection in May 2013 at Tongji Hospital in China. Despite with the undetectable virus DNA in serum, we determined the pattern of viral integration in tumor cells and adjacent non-tumor cells and obtained the details of the viral arrangement in host genome, and furthermore the HBV integrated region in cancer genome. Results: HBV captured sequencing of tissues and individual cells revealed that samples from multiple tumors shared two viral integration sites that could affect three host genes, including CSMD2 on chr1 and MED30/EXT1 on chr8. Whole genome sequencing further indicated one hybrid chromosome formed by HBV integrations between chr1 and chr8 that was shared by multiple tumors. Additional 50 poorly differentiated liver tumors and the paired adjacent non-tumors were evaluated and functional studies suggested up-regulated EXT1 expression promoted HCC growth. We further observed that the most somatic mutations within the tumor cell genome were common among the multiple tumors, suggesting that HBV associated, multifocal HCC is monoclonal in origin. Conclusion: Through analyzing the HBV integration sites in multifocal HCC, our data suggested that the tumor cells were monoclonal in origin and formed in the absence of active viral replication, whereas the affected host genes may subsequently contribute to carcinogenesis.
AB - Background & Aims: Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We studied the mechanism of life-long Integration of virus DNA into OBI host's genome, of which may induce hepatocyte transformation. Methods: We applied HBV capture sequencing on single cells from an OBI patient who, developed multiple HCC tumors and underwent liver resection in May 2013 at Tongji Hospital in China. Despite with the undetectable virus DNA in serum, we determined the pattern of viral integration in tumor cells and adjacent non-tumor cells and obtained the details of the viral arrangement in host genome, and furthermore the HBV integrated region in cancer genome. Results: HBV captured sequencing of tissues and individual cells revealed that samples from multiple tumors shared two viral integration sites that could affect three host genes, including CSMD2 on chr1 and MED30/EXT1 on chr8. Whole genome sequencing further indicated one hybrid chromosome formed by HBV integrations between chr1 and chr8 that was shared by multiple tumors. Additional 50 poorly differentiated liver tumors and the paired adjacent non-tumors were evaluated and functional studies suggested up-regulated EXT1 expression promoted HCC growth. We further observed that the most somatic mutations within the tumor cell genome were common among the multiple tumors, suggesting that HBV associated, multifocal HCC is monoclonal in origin. Conclusion: Through analyzing the HBV integration sites in multifocal HCC, our data suggested that the tumor cells were monoclonal in origin and formed in the absence of active viral replication, whereas the affected host genes may subsequently contribute to carcinogenesis.
KW - Hepatitis B
KW - Hepatocellular carcinoma
KW - Single-cell sequencing
KW - Viral integration
KW - Virome capture sequencing
KW - Whole genome sequencing
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U2 - 10.1186/s13046-019-1273-1
DO - 10.1186/s13046-019-1273-1
M3 - RGC 21 - Publication in refereed journal
C2 - 31200735
SN - 0392-9078
VL - 38
JO - Journal of Experimental and Clinical Cancer Research
JF - Journal of Experimental and Clinical Cancer Research
M1 - 261
ER -