Dataset Information

Genentech whole genome and transcriptome sequencing of four hepatocellular carcinoma patients

ABSTRACT:

Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). In this study we sequenced the whole genome (~80X) and transcriptome of tumor and non-tumor samples from four HCC patients and identified over two hundred HBV integration sites. We found significant clonal expansion of HBV-integrated hepatocytes specifically in the tumor samples. We observed a diverse collection of genomic perturbations near viral integration sites, including gene disruption, viral promoter-driven human transcription, viral-human transcript fusion and DNA copy number alteration. We also sequenced one patient at ultra-high coverage (~240X) to build the most comprehensive HBV-integration landscape yet attempted. Our data suggest that the viral integration significantly expands carcinogenic opportunities in HBV-infected individuals.

PROVIDER: phs000384.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients.

Jiang Zhaoshi Z Jhunjhunwala Suchit S Liu Jinfeng J Haverty Peter M PM Kennemer Michael I MI Guan Yinghui Y Lee William W Carnevali Paolo P Stinson Jeremy J Johnson Stephanie S Diao Jingyu J Yeung Stacy S Jubb Adrian A Ye Weilan W Wu Thomas D TD Kapadia Sharookh B SB de Sauvage Frederic J FJ Gentleman Robert C RC Stern Howard M HM Seshagiri Somasekar S Pant Krishna P KP Modrusan Zora Z Ballinger Dennis G DG Zhang Zemin Z

Genome research 20120120 4

Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC). HBV integration into the host genome has been reported, but its scale, impact and contribution to HCC development is not clear. Here, we sequenced the tumor and nontumor genomes (>80× coverage) and transcriptomes of four HCC patients and identified 255 HBV integration sites. Increased sequencing to 240× coverage revealed a proportionally higher number of integration sites. Clonal expansion of HBV-integ ...[more]

PMID: 22267523

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Project description:Although hepatitis B virus (HBV) has been established to cause hepatocellular carcinoma (HCC), the exact mechanism remains to be clarified. Type II ground glass hepatocytes (GGH) harboring the HBV pre-S2 mutant large surface protein have been recognized as morphologically distinct hallmark of HCC in advanced stages of chronic HBV infection. Considering its pre-neoplastic nature, we hypothesized that type II GGH may exhibit high genomic instability, which is important for the carcinogenic process in chronic HBV carriers. In this study we found that pre-S2 mutant LHBS directly interacted with importin 1, the key factor that recognizes cargos undergoing nuclear transportation mediated by the importin 1 associated nuclear pore complex (NPC). By interacting with importin 1, which inhibits its function as an NPC factor, pre-S2 mutant LHBS blocked nuclear transportation of an essential DNA repair and recombination factor Nijmegen breakage syndrome 1 (NBS1) upon DNA damage, thereby delaying formation of nuclear foci at the sites of DNA double strand breaks. Pre-S2 mutant LHBS was also found to block NBS1-mediated homologous recombination repair and induce multi-nucleation of cells. In addition, pre-S2 mutant LHBS transgenic mice showed genomic instability indicated by increased global gene copy number variations (CNV), which were significantly higher than those in hepatitis B virus X mice, indicating that pre-S2 mutant LHBS is the major viral oncoprotein inducing genomic instability in HBV-infected hepatocytes. Consistently, the human type II GGHs in HCC patients exhibited increased DNA double-strand breaks representing significant genomic instability. In conclusion, type II GGH harboring HBV pre-S2 mutant oncoprotein represents a high-risk marker for the loss of genome integrity in chronic HBV carriers and explains the complex chromosome changes in HCCs. Non-tumorous liver sections from four each the HBx and pre-S2 mutant LHBS transgenic mice and 3 double transgenic mice between 9 and 22 months old were examined for gene gain and loss.

Dataset Information

Genentech whole genome and transcriptome sequencing of four hepatocellular carcinoma patients

Publications

The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients.

Similar Datasets

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