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.

Author information

Author notes

    • Meng Li
    •  & Hong Zhao

    These authors contributed equally to this work.

Affiliations

  1. Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Meng Li
    • , Victor E Velculescu
    • , Shibin Zhou
    • , Bert Vogelstein
    • , Nick Papadopoulos
    •  & Kenneth W Kinzler
  2. Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Hong Zhao
    •  & Jianqiang Cai
  3. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Xiaosong Zhang
  4. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Laura D Wood
    • , Robert A Anders
    • , Hubert D Daniel
    • , Rajesh Kannangai
    • , Ralph H Hruban
    •  & Michael S Torbenson
  5. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Michael A Choti
    •  & Timothy M Pawlik
  6. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

    • G Johan A Offerhaus
  7. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Linfang Wang

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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.

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.

Corresponding authors

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

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    Supplementary Text and Figures

    Supplementary Methods, Supplementary Figures 1 and 2 and Supplementary Tables 1–8.

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DOI

https://doi.org/10.1038/ng.903

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