Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

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Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in 50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.

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Figure 1: Somatic substitution patterns of HCCs.
Figure 2: Mutation patterns of MCTs.
Figure 3: Mutant allele proportions of point mutations.
Figure 4: Mutations in chromatin regulators and functional analysis of potential driver genes.
Figure 5: Clonal proportion of HBV integration sites in cancer cell populations of four HBV-integrated HCCs.

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NCBI Reference Sequence

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Acknowledgements

The supercomputing resource SHIROKANE was provided by the Human Genome Center at The University of Tokyo. The authors thank T. Urushidate, S. Ohashi, N. Okada, A. Kokubu and H. Shimizu at the National Cancer Center Research Institute and C. Inai, R. Ooishi, and R. Kitada at the RIKEN Center for Genomic Medicine for their technical assistances. This work was supported partially by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), the National Cancer Center Research and Development Fund (23-A-8) and the RIKEN Strategic Research Program for R&D of President's Fund 2011.

Author information

A.F., Y.T., T.A., K.A.B., F.M., H. Nakamura, T.T., T. Shibata and H. Nakagawa performed data analyses. F.H., Y.A., H. Takahashi, T. Shirakihara, K.N., K.W.-M., T. Shibata and H. Nakagawa performed whole-genome sequencing. F.H., H.H.N., K.N. and K.W.-M. performed the validation sequencing study. F.H., Y.A., H. Takahashi, T. Shirakihara and T. Shibata performed siRNA experiments. A.F., M.A., N.H. and M.K. performed digital PCR and SNP microarray experiments. M.N., T. Shibuya, H. Tanaka and S.M. operated the supercomputer system. H. Ojima, K.S., T.O., M.U., Y.S., Y.K., K.A., H. Ohdan, K.G., O.I., S.A., M.Y., T.Y., K.C., T.K. and H.Y. collected clinical samples. A.F., Y.T., T.T., T. Shibata and H. Nakagawa wrote the manuscript. Y.N., T.T., T. Shibata and H. Nakagawa conceived the study and led the design of the experiments. J.K., N.K., H. Nakagama, Y.N., T. Shibata and H. Nakagawa contributed to the findings for this study.

Correspondence to Tatsuhiro Shibata or Hidewaki Nakagawa.

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Fujimoto, A., Totoki, Y., Abe, T. et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 44, 760–764 (2012) doi:10.1038/ng.2291

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