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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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).
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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.
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Supplementary Note, Supplementary Figures 1–35, Supplementary Tables 1, 2, 4–6 and 13–32. (PDF 8833 kb)
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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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DOI: https://doi.org/10.1038/ng.3126
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