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Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer

Nature Genetics volume 48, pages 500–509 (2016)Cite this article

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An Erratum to this article was published on 27 May 2016

This article has been updated

Abstract

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

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Figure 1: Summary of mutations and recurrently mutated features in 300 liver cancer whole genomes.
Figure 2: Genome-wide mutational signatures of 300 liver cancers.
Figure 3: Mutations in annotated noncoding regions.
Figure 4: Genome-wide search for mutational clusters in noncoding regions.
Figure 5: Analysis of structural variations and their effect on gene expression.
Figure 6: Clinical implications and association with prognosis.

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Change history

  • 18 April 2016

    In the version of this article initially published online, the mutation category plots in the top panel of Figure 1 were not correctly aligned with the corresponding genes. In addition, the labels for tumor types on the left were not correctly aligned with individual samples. The errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

The supercomputing resource 'SHIROKANE' was provided by the Human Genome Center at The University of Tokyo. This work was supported in part by RIKEN President's Fund 2011, a Grant-in-Aid for the RIKEN CGM and IMS, a Grant-in-Aid for Scientific Research on Innovative Areas from JSPS grants (25134717, 25670375, 23114001, and 15H04814), the Princess Takamatsu Cancer Research Fund, the Takeda Science Foundation, the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development, CREST from the Japan Science and Technology Agency, and National Cancer Center Research and Development Funds (26-A-5); the National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan.

Author information

Author notes

  1. Akihiro Fujimoto, Mayuko Furuta, Yasushi Totoki, Tatsuhiko Tsunoda and Mamoru Kato: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan

    Akihiro Fujimoto, Mayuko Furuta, Hiroaki Taniguchi, Christopher P Wardell, Kaoru Nakano, Kazuhiro Maejima, Aya Sasaki-Oku, Ayako Ohsawa & Hidewaki Nakagawa

  2. Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.,

    Yasushi Totoki, Hiromi Nakamura, Natsuko Hama, Fumie Hosoda, Yasuhito Arai, Shoko Ohashi & Tatsuhiro Shibata

  3. Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Tatsuhiko Tsunoda, Keith A Boroevich & Tetsuo Abe

  4. Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    Tatsuhiko Tsunoda

  5. CREST, JST, Tokyo, Japan

    Tatsuhiko Tsunoda & Mamoru Kato

  6. Department of Bioinformatics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.,

    Mamoru Kato

  7. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yuichi Shiraishi, Hiroko Tanaka & Satoru Miyano

  8. Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima, Japan

    Yoshiiku Kawakami, Hiroshi Aikata & Kazuki Chayama

  9. Second Department of Surgery, Wakayama Medical University, Wakayama, Japan

    Masaki Ueno, Shinya Hayami & Hiroki Yamaue

  10. Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

    Kunihito Gotoh, Shigeru Marubashi, Terumasa Yamada & Osamu Ishikawa

  11. Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan

    Shun-ichi Ariizumi & Masakazu Yamamoto

  12. Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Toru Nakamura & Satoshi Hirano

  13. Department of Anatomical Pathology, Hiroshima University School of Medicine, Hiroshima, Japan

    Koji Arihiro

  14. Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Tetsuo Shibuya & Satoru Miyano

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

    Tomoko Urushidate & Tatsuhiro Shibata

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

    Genta Nagae, Shogo Yamamoto, Hiroki Ueda, Kenji Tatsuno & Hiroyuki Aburatani

  17. Department of Pathology, Keio University School of Medicine, Shinjyuku-ku, Tokyo, Japan

    Hidenori Ojima

  18. Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.,

    Nobuyoshi Hiraoka

  19. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.,

    Takuji Okusaka

  20. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Michiaki Kubo

  21. Department of Gastroenterological Surgery, Hiroshima University School of Medicine, Hiroshima, Japan

    Hideki Ohdan

  22. Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.,

    Kazuaki Shimada

  23. Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan

    Kazuki Chayama

Authors
  1. Akihiro Fujimoto
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  2. Mayuko Furuta
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Contributions

Study design: H. Nakagawa and T. Shibata. Data acquisition and management: H. Tanaka, K.A.B., T.A., K.N., K.M., A.S.-O., A.O., T. Shibuya, F.H., Y.A., S.O., T.U., M. Kubo, S. Miyano, and H. Nakagawa. Data analysis: A.F., M.F., Y.T., T.T., M. Kato, Y.S., H. Tanaka, C.P.W., H. Nakamura, N. Hama, G.N., S.Y., H.U., and K.T. Molecular analysis: M.F. and H. Taniguchi. Sample acquisition and clinical data collection: Y.K., M.U., K.G., S.A., S. Hayami, T.N., H. Aikata, K.A., H. Ojima, N. Hiraoka, T.O., S. Marubashi, T.Y., S. Hirano, M.Y., H. Ohdan, K.S., O.I., H.Y., and K.C. Manuscript writing: A.F., M.F., Y.T., T.T., M. Kato, C.P.W., K.A.B., T. Shibata, and H. Nakagawa. Project supervision: H. Nakagawa, T. Shibata, H. Aburatani, and S. Miyano.

Corresponding authors

Correspondence to Tatsuhiro Shibata or Hidewaki Nakagawa.

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The authors declare no competing financial interests.

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Fujimoto, A., Furuta, M., Totoki, Y. et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet 48, 500–509 (2016). https://doi.org/10.1038/ng.3547

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