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Trans-ancestry mutational landscape of hepatocellular carcinoma genomes

Nature Genetics volume 46, pages 1267–1273 (2014)Cite this article

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Abstract

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.

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Figure 1: Multiple types of TERT alterations in HCC.
Figure 2: Significant cancer driver genes in HCC.
Figure 3: Oncogenic network in HCC.
Figure 4: Somatic substitution patterns were associated with ancestry.
Figure 5: Ancestry-specific mutational signatures with transcriptional strand bias in the HCC genome.

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Acknowledgements

This study was supported by Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan for the third-term Comprehensive 10-Year Strategy for Cancer Control, grants from the US National Human Genome Research Institute (NHGRI; 5U54HG003273) and National Cancer Institute (NCI; HHSN261201000053C and P30 CA125123), the Program for Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation (NIBIO, Japan) and the National Cancer Center Research and Development Funds (23-A-8, Japan). The National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan. The supercomputing resource SHIROKANE was provided by the Human Genome Center at the University of Tokyo (http://sc.hgc.jp/shirokane.html).

Author information

Author notes

  1. Yasushi Totoki, Kenji Tatsuno and Kyle R Covington: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan

    Yasushi Totoki, Mamoru Kato, Hiromi Nakamura, Natsuko Hama, Fumie Hosoda, Yasuhito Arai, Tomoko Urushidate, Shoko Ohashi, Naoko Okada & Tatsuhiro Shibata

  2. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

    Kenji Tatsuno, Hiroki Ueda, Shingo Tsuji, Shogo Yamamoto, Kengo Gotoh, Genta Nagae, Akimasa Hayashi & Hiroyuki Aburatani

  3. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA

    Kyle R Covington, Chad J Creighton, Eve Shinbrot, Megan Lehmkuhl, Kim Walker, Mahmoud Dahdouli, Marie-Claude Gingras, Donna M Muzny, Harsha Doddapaneni, Min Wang, Yiming Zhu, Huyen Dinh, Richard A Gibbs & David A Wheeler

  4. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

    Chad J Creighton

  5. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA

    Lawrence A Donehower & Betty L Slagle

  6. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan

    Hidenori Ojima

  7. Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan

    Kazuaki Shimada & Tomoo Kosuge

  8. Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan

    Yutaka Midorikawa & Tadatoshi Takayama

  9. Department of Surgery, Baylor College of Medicine, Houston, Texas, USA

    John A Goss, Ronald Cotton & Jacfranz Guiteau

  10. Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Akimasa Hayashi, Junji Shibahara, Shumpei Ishikawa, Mariko Tanaka & Masashi Fukayama

  11. Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan

    Takuji Okusaka

  12. Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Norihiro Kokudo

  13. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Tatsuhiro Shibata

Authors
  1. Yasushi Totoki
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  2. Kenji Tatsuno
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  4. Hiroki Ueda
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  6. Mamoru Kato
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  8. Lawrence A Donehower
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  16. Yasuhito Arai
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  45. Richard A Gibbs
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  46. David A Wheeler
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  48. Tatsuhiro Shibata
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Contributions

Study design: Y.T., K.T., K.R.C., H.U., M.K., D.A.W., H.A. and T.S. Sequencing data generation: K.T., D.M.M., F.H., H. Doddapaneni, H. Dinh, Y.A., K.G., K.W., M.-C.G., T.U., S.O., N.O., M.W. and Y.Z. Data analysis: Y.T., K.T., K.R.C., H.U., M.K., S.T., L.A.D., B.L.S., E.S., S.Y., H.N., M.L., N.H., K.W., K.G., M.D., G.N., D.A.W. and T.S. Statistical analysis: Y.T., K.R.C., H.U., K.T., C.J.C., M.K., S.T. and S.Y. Molecular analysis: Y.A. and T.S. Sample acquisition and clinical data collection: M.-C.G., K.S., Y.M., J.A.G., H.O., A.H., J.S., R.C., J.G., S.I., M.T., T.O., N.K., T.K., T.T. and M.F. Manuscript writing: Y.T., K.T., K.R.C., H.U., C.J.C., L.A.D., B.L.S., M.K., D.A.W., H.A. and T.S. Project oversight: D.A.W., R.A.G., H.A. and T.S.

Corresponding authors

Correspondence to David A Wheeler, Hiroyuki Aburatani or Tatsuhiro Shibata.

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Competing interests

The authors declare no competing financial interests.

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Totoki, Y., Tatsuno, K., Covington, K. et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet 46, 1267–1273 (2014). https://doi.org/10.1038/ng.3126

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