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Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma.

ABSTRACT: Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis. Here by conducting high-throughput viral integration detection and RNA sequencing, we identify 4,225 HBV integration events in tumour and adjacent non-tumour samples from 426 patients with HCC. We show that HBV is prone to integrate into rare fragile sites and functional genomic regions including CpG islands. We observe a distinct pattern in the preferential sites of HBV integration between tumour and non-tumour tissues. HBV insertional sites are significantly enriched in the proximity of telomeres in tumours. Recurrent HBV target genes are identified with few that overlap. The overall HBV integration frequency is much higher in tumour genomes of males than in females, with a significant enrichment of integration into chromosome 17. Furthermore, a cirrhosis-dependent HBV integration pattern is observed, affecting distinct targeted genes. Our data suggest that HBV integration has a high potential to drive oncogenic transformation.

SUBMITTER: Zhao LH

PROVIDER: S-EPMC5059470 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma.

Zhao Ling-Hao LH Liu Xiao X Yan He-Xin HX Li Wei-Yang WY Zeng Xi X Yang Yuan Y Zhao Jie J Liu Shi-Ping SP Zhuang Xue-Han XH Lin Chuan C Qin Chen-Jie CJ Zhao Yi Y Pan Ze-Ya ZY Huang Gang G Liu Hui H Zhang Jin J Wang Ruo-Yu RY Yang Yun Y Wen Wen W Lv Gui-Shuai GS Zhang Hui-Lu HL Wu Han H Huang Shuai S Wang Ming-Da MD Tang Liang L Cao Hong-Zhi HZ Wang Ling L Lee Tin-Lap TL Jiang Hui H Tan Ye-Xiong YX Yuan Sheng-Xian SX Hou Guo-Jun GJ Tao Qi-Fei QF Xu Qin-Guo QG Zhang Xiu-Qing XQ Wu Meng-Chao MC Xu Xun X Wang Jun J Yang Huan-Ming HM Zhou Wei-Ping WP Wang Hong-Yang HY

Nature communications 20161005

Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis. Here by conducting high-throughput viral integration detection and RNA sequencing, we identify 4,225 HBV integration events in tumour and adjacent non-tumour samples from 426 patients with HCC. We show that HBV is prone to integrate into rare fragile sites and functional genomic regions including CpG islands. We observe a distinct pattern in the preferential sites of HBV int ...[more]

PMID: 27703150

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Project description:Infection by chronic hepatitis B virus (HBV) is one of the major causes of liver cirrhosis and primary hepatocellular carcinoma (HCC). Viral DNA integration into the host cell genome is a key mechanism of hepatocarcinogenesis. However, the molecular characterization and the potential clinical implications of HBV DNA integration into patients suffering from different hepatitis and HCC remain unclear. In this study, we analyzed HBV integrations in patients with hepatitis B and HCC using HBV probe-based capturing and next-generation sequencing. The results revealed that the sizes of the HBV integrations ranged from 28 bp to 3215 bp, including the full-length HBV DNA sequence. The integration breakpoints were preferentially distributed in the viral enhancer, X protein, and core protein regions of the HBV genome. The number of HBV integrations followed an increasing trend from hepatitis to HCC, which was positively correlated with the HBV virus load in patients with hepatitis. The number of HBV integrations in the HBeAg positive chronic hepatitis B group was significantly greater than that in the other hepatitis B groups (P < 0.05). However, the relative abundance of HBV integrations was significantly higher in HCC tissues than in the adjacent liver tissues. Interestingly, 61.6% (8/13) of HBV-human DNA integration fragments could be detected at the RNA level. Our results also showed that HBV integration-targeted genes (ITGs) were significantly enriched in many cancer-related pathways, such as MAPK, extracellular matrix (ECM)-receptor interaction, and the hedgehog signaling pathway. Individuals with HBV integrations exhibited shorter disease-free survival (DFS) and overall survival (OS) than those without HBV integrations in some ITGs including LINC00293 (long intergenic non-protein coding RNA 293; DFS P = 0.008, OS P = 0.009), FSHB (follicle stimulating hormone beta subunit; DFS P = 0.05, OS P = 0.186), and LPHN3 (latrophilin-3; DFS P = 0.493, OS P = 0.033). This study determined the underlying mechanism of HBV DNA integration in liver diseases and laid the foundation for future studies on the pathogenesis of liver cancer.

Dataset Information

Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma.

Publications

Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma.

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