Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma

Abstract

To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥ 4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival.

Mutational landscape of intrahepatic cholangiocarcinoma

“…Among these genes, ARID1A encodes a component of SWI/SNF chromatin remodelling complex and is also frequently mutated in HCC. In addition, genes encoding histone methyltransferase such as KMT2A/MLL, KMT2B/MLL2, KMT2D/MLL4 are also found mutated in eight ICC patients in this study, as reported in other cancer genome sequencing studies 12,19,54,59 . Among 102 ICC patients in our cohort, five (4.9%) harbours mutations in IDH1, and all mutations cluster in a previously reported hotspot (codon 132).…”

“…Many large-scale genome sequencing projects have been executed to identify how somatic mutations [11][12][13][14][15][16][17][18] and hepatitis B virus (HBV) integration [19][20][21] affect HCC patients. In contrast, large-scale genome sequencing projects targeting the ICC cancer genomes just started to catch up.…”

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

“…For HBV (a DNA virus), there is also evidence of viral integration, leading to expression of HBV-associated antigens in tumor cells (5)(6)(7). Early stage HCC can be cured by tumor ablation, resection, or liver transplantation, but most patients have more advanced disease at diagnosis (8,9).…”

C-terminal-truncated hepatitis B virus X protein enhances the development of diethylnitrosamine-induced hepatocellular carcinogenesis

“…Recent studies using next-generation sequencing technologies have highlighted the fact that, following the integration of HBV into the cellular genome, the 39-end of the HBx gene is often deleted and this event is observed more frequently in tumour tissues (Jiang et al, 2012;Sung et al, 2012;Toh et al, 2013). Furthermore, truncated HBx human chimeric transcripts may be seen and expressed as chimeric proteins (Sirma et al, 1999;Toh et al, 2013;Tu et al, 2001).…”

“…These include hot-spot mutations in HBx at aa 130 and 131, which have been associated with the development of HCC (Iavarone et al, 2003;Kuang et al, 2004;Lee et al, 2011). Furthermore, the random integration of HBV DNA into the host genome frequently leads to 39-end-deleted sequences of the HBx gene and the observation of chimeric transcripts which often carry deletions at the 39-end of HBx gene, resulting in C-terminal-truncated HBx protein (Iavarone et al, 2003;Jiang et al, 2012;Ma et al, 2008;Sirma et al, 1999;Sung et al, 2012;Sze et al, 2013;Toh et al, 2013;Tu et al, 2001). Interestingly, a recent study with human HCC samples reports an association between the presence of C-terminal truncation of HBx and venous invasion (Sze et al, 2013).…”