Long read sequencing reveals sequential complex rearrangements driven by Hepatitis B virus integration

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Integration of Hepatitis B virus (HBV) into human genome disrupts genetic structures and cellular functions. Here, we conducted multiplatform long read sequencing on two cell lines and five clinical samples of HBV-infected hepatocellular carcinomas (HCC). We resolved three types of viral integration-induced complex genome rearrangements (CGR) and proposed a model of ‘multi-hits and sequential-breaks’ to depict their formation process by differentiating inserted HBV copies with HiFi long reads. We deduced that all three complex types were initialized from focal replacement and fragile virus-human junctions triggered subsequent rearrangements. We further revealed that such rearrangements caused a prevalent loss-of-heterozygosity at chr4q, accounting for 19.5% of HCC samples in ICGC cohort and contributing to immune and metabolic dysfunction. Overall, our long read based analysis reveals novel sequential rearrangement processes initiated by HBV integration, hinting its structural and functional impact on HCC.

Authors 9

1. Songbo Wang

   Xi'an Jiaotong University

   Affiliation as printed

   MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

   School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

2. Jiadong Lin

   Xi'an Jiaotong University

   Affiliation as printed

   MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

   School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

3. Xiaofei Yang

   Xi'an Jiaotong University

   Affiliation as printed

   MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

   School of Computer Science and Technology, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

4. Zihang Li

   Xi'an Jiaotong University

   Affiliation as printed

   School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, China

5. Tun Xu

   Xi'an Jiaotong University

   Affiliation as printed

   MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

   School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

6. Tingjie Wang

   Xi'an Jiaotong University

   Affiliation as printed

   MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

   School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

7. Bo Wang

   First Affiliated Hospital of Xi'an Jiaotong University · Xi'an Jiaotong University

   Affiliation as printed

   The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China

8. Liangshuo Hu

   First Affiliated Hospital of Xi'an Jiaotong University · Xi'an Jiaotong University

   Affiliation as printed

   The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China

9. Kai Ye corresponding Aachen Faculty of Science, Leiden University

   Leiden University · First Affiliated Hospital of Xi'an Jiaotong University · Xi'an Jiaotong University

   Affiliation as printed

   Faculty of Science, Leiden University, Leiden, The Netherlands

   Genome Institute, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China

   MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

   School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

   School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, China