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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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.
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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.
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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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DOI: https://doi.org/10.1038/ng.3547
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