Department   School of Medicine(Tokyo Women's Medical University Hospital), School of Medicine
   Position   Associate Professor
Article types Original article
Language English
Peer review Non peer reviewed
Title Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers.
Journal Formal name:Oncotarget
ISSN code:19492553/19492553
Domestic / ForeginForegin
Volume, Issue, Page 9(38),pp.25075-25088
Author and coauthor Furuta Mayuko, Tanaka Hiroko, Shiraishi Yuichi, Unida Takuro, Imamura Michio, Fujimoto Akihiro, Fujita Masahi, Sasaki-Oku Aya, Maejima Kazuhiro, Nakano Kaoru, Kawakami Yoshiiku, Arihiro Koji, Aikata Hiroshi, Ueno Masaki, Hayami Shinya, Ariizumi Shun-Ichi, Yamamoto Masakazu, Gotoh Kunihito, Ohdan Hideki, Yamaue Hiroki, Miyano Satoru, Chayama Kazuaki, Nakagawa Hidewaki
Publication date 2018/05
Summary Integration of Hepatitis B virus (HBV) into the human genome can cause genetic instability, leading to selective advantages for HBV-induced liver cancer. Despite the large number of studies for HBV integration into liver cancer, little is known about the mechanism of initial HBV integration events owing to the limitations of materials and detection methods. We conducted an HBV sequence capture, followed by ultra-deep sequencing, to screen for HBV integrations in 111 liver samples from human-hepatocyte chimeric mice with HBV infection and human clinical samples containing 42 paired samples from non-tumorous and tumorous liver tissues. The HBV infection model using chimeric mice verified the efficiency of our HBV-capture analysis and demonstrated that HBV integration could occur 23 to 49 days after HBV infection via microhomology-mediated end joining and predominantly in mitochondrial DNA. Overall HBV integration sites in clinical samples were significantly enriched in regions annotated as exhibiting open chromatin, a high level of gene expression, and early replication timing in liver cells. These data indicate that HBV integration in liver tissue was biased according to chromatin accessibility, with additional selection pressures in the gene promoters of tumor samples. Moreover, an integrative analysis using paired non-tumorous and tumorous samples and HBV-related transcriptional change revealed the involvement of TERT and MLL4 in clonal selection. We also found frequent and non-tumorous liver-specific HBV integrations in FN1 and HBV-FN1 fusion transcript. Extensive survey of HBV integrations facilitates and improves the understanding of the timing and biology of HBV integration during infection and HBV-related hepatocarcinogenesis.
DOI 10.18632/oncotarget.25308
PMID 29861854