Abstract

The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC, we performed a near-saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers and a very large number (2,860) of candidate later stage drivers that were enriched for genes that are mutated, deregulated or functioning in signaling pathways important for human HCC, with a striking 1,199 genes being linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC.

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Acknowledgements

We acknowledge K. Reifenberg at Johannes Gutenberg University, Germany, for giving us the HBsAg mouse strain (originated from F. Chisari). We also thank K. Rogers and S. Rogers at the Institute of Molecular and Cell Biology Histopathology core for their necropsy and histotechnology assistance. We thank P. Cheok, N. Lim and D. Chen for their help with mouse breeding and monitoring. This work was supported by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore and the Cancer Prevention Research Institute of Texas (CPRIT). A.G.R. and D.J.A. are supported by the Wellcome Trust and Cancer Research UK. N.A.J. and N.G.C. are both CPRIT Scholars in Cancer Research.

Author information

Author notes

    • Nancy A Jenkins
    •  & Neal G Copeland

    Present address: The Methodist Hospital Research Institute, Houston, Texas, USA.

    • Nancy A Jenkins
    •  & Neal G Copeland

    These authors contributed equally to this work.

Affiliations

  1. Institute Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.

    • Emilie A Bard-Chapeau
    • , Anh-Tuan Nguyen
    • , Ahmed Sayadi
    • , Belinda Q Chua
    • , Jerrold M Ward
    • , Christopher K Y Chin
    • , Frederic A Bard
    • , Nancy A Jenkins
    •  & Neal G Copeland
  2. Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Alistair G Rust
    •  & David J Adams
  3. Clinical Imaging Research Centre, National University of Singapore, Centre for Translation Medicine, Singapore Bioimaging Consortium, Singapore.

    • Philip Lee
    •  & George K Radda
  4. Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.

    • Lee-Sun New
    •  & Eric Chun Yong Chan
  5. Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

    • Johann de Jong
    •  & Lodewyk F A Wessels
  6. Singapore Immunology Network (SIgN), A*STAR, Biopolis, Singapore.

    • Valerie Chew
    •  & Jean-Pierre Abastado
  7. National Cancer Centre, Singapore.

    • Han Chong Toh
  8. Cancer Science Institute of Singapore, National University of Singapore, Singapore.

    • Touati Benoukraf
    •  & Richie Soong
  9. Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.

    • Adam J Dupuy
  10. Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Randy L Johnson

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Contributions

E.A.B.-C. performed the majority of experiments, designed experiments, analyzed data and wrote the manuscript. A.-T.N. performed experiments, analyzed data and wrote the manuscript. A.G.R. and D.J.A. sequenced the samples and processed and analyzed data. A.S., C.K.Y.C., T.B., R.S. and F.A.B. performed computational analyses. B.Q.C. executed experiments. E.C.Y.C. and L.-S.N. performed the metabolomics study. P.L. and G.K.R. carried out in vivo metabolic imaging and metabolic assays. J.M.W. analyzed mouse hepatic pathology. J.-P.A., V.C. and H.C.T. provided and processed human patient samples. A.J.D. helped analyze data, and R.L.J. carried out the liver-SB screen in the Sav1 mutant background. J.d.J. and L.F.A.W. revised statistics and performed analyses. N.G.C. and N.A.J. designed the study, analyzed the data and wrote the manuscript. All authors commented on and edited the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Neal G Copeland.

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https://doi.org/10.1038/ng.2847

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