Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers
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Mayuko Furuta1, Hiroko Tanaka2, Yuichi Shiraishi2, Takuro Uchida3, Michio Imamura3, Akihiro Fujimoto1, Masahi Fujita1, Aya Sasaki-Oku1, Kazuhiro Maejima1, Kaoru Nakano1, Yoshiiku Kawakami3, Koji Arihiro4, Hiroshi Aikata3, Masaki Ueno5, Shinya Hayami5, Shun-Ichi Ariizumi6, Masakazu Yamamoto6, Kunihito Gotoh7, Hideki Ohdan8, Hiroki Yamaue5, Satoru Miyano2, Kazuaki Chayama3 and Hidewaki Nakagawa1
1Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan
2Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
3Department of Gastroenterology and Metabolism, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
4Department of Anatomical Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
5Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan
6Department of Gastroenterological Surgery, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
7Department of Surgery, Osaka International Cancer Institute, Osaka 537-8511, Japan
8Department of Gastroenterological Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
Hidewaki Nakagawa, email: firstname.lastname@example.org
Kazuaki Chayama, email: email@example.com
Keywords: HBV; liver cancer; sequencing; genome integration; mitochondria
Received: December 05, 2017 Accepted: April 06, 2018 Published: May 18, 2018
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.
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