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Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma

Abstract

Through exomic sequencing of ten hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCC) and subsequent evaluation of additional affected individuals, we discovered novel inactivating mutations of ARID2 in four major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivation mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype.

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Acknowledgements

We thank N. Silliman, J. Ptak, L. Dobbyn, J. Schaeffer, M. Whalen, Z. Khan, J. Ma, Z. Wang and R. Mi for expert technical assistance. This work was supported by The Virginia and D.K. Ludwig Fund for Cancer Research and US National Institutes of Health grants CA43460, CA57345, CA62924, CA121113, DK078686, DK080736, DK081417, AACR Stand Up to Cancer Dream Team Translational Cancer Research Grant and National Science and Technology Major Project Grant 2008ZX10002-025.

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Authors and Affiliations

Authors

Contributions

M.L., B.V., K.W.K., S.Z., M.S.T. and R.H.H. designed the study. M.S.T., J.C., H.Z., S.Z., M.L., L.W., X.Z., L.D.W., R.A.A., M.A.C., T.M.P., H.D.D., R.K., G.J.A.O., R.H.H., V.E.V. and B.V. collected and analyzed the HCC samples. M.L., N.P. and K.W.K. performed genomic sequencing. M.L., K.W.K., B.V. and N.P. analyzed the genetic data. M.L., B.V. and K.W.K. wrote draft manuscripts. All authors contributed to the final version of the paper.

Corresponding authors

Correspondence to Jianqiang Cai, Michael S Torbenson or Kenneth W Kinzler.

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Competing interests

Under agreements between the Johns Hopkins University, Genzyme, Exact Sciences, Inostics, QIAGEN, Invitrogen and Personal Genome Diagnostics, N.P., B.V., K.W.K. and V.E.V. are entitled to a share of the royalties received by the University on sales of products related to genes described in this manuscript. N.P., B.V., K.W.K. and V.E.V. are cofounders of Inostics and Personal Genome Diagnostics, are members of their Scientific Advisory Boards and own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy.

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Supplementary Methods, Supplementary Figures 1 and 2 and Supplementary Tables 1–8. (PDF 750 kb)

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Li, M., Zhao, H., Zhang, X. et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 43, 828–829 (2011). https://doi.org/10.1038/ng.903

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