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Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR

Authors

  • Vincent W. Keng,

    Corresponding author
    1. Masonic Cancer Center, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Department of Genetics, Cell Biology and Development, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    3. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    4. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
    • Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
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    • fax: 612-626-2600

  • Daniela Sia,

    1. HCC Translational Research Lab, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, IRCSS Foundation, Milan, Italy
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  • Aaron L. Sarver,

    1. Masonic Cancer Center, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Biostatistics and Bioinformatics, University of Minnesota, Minneapolis, Minnesota
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  • Barbara R. Tschida,

    1. Masonic Cancer Center, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Department of Genetics, Cell Biology and Development, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    3. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
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  • Danhua Fan,

    1. Masonic Cancer Center, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Biostatistics and Bioinformatics, University of Minnesota, Minneapolis, Minnesota
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  • Clara Alsinet,

    1. HCC Translational Research Lab, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
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  • Manel Solé,

    1. HCC Translational Research Lab, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
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  • Wai L. Lee,

    1. Department of Genetics, Cell Biology and Development, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
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  • Timothy P. Kuka,

    1. Department of Genetics, Cell Biology and Development, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
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  • Branden S. Moriarity,

    1. Masonic Cancer Center, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Department of Genetics, Cell Biology and Development, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    3. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
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  • Augusto Villanueva,

    1. HCC Translational Research Lab, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
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  • Adam J. Dupuy,

    1. University of Iowa, Iowa City, Iowa
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  • Jesse D. Riordan,

    1. University of Iowa, Iowa City, Iowa
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  • Jason B. Bell,

    1. Masonic Cancer Center, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
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  • Kevin A. T.Silverstein,

    1. Masonic Cancer Center, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Biostatistics and Bioinformatics, University of Minnesota, Minneapolis, Minnesota
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  • Josep M. Llovet,

    1. HCC Translational Research Lab, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York City, New York
    3. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
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  • David A. Largaespada

    Corresponding author
    1. Masonic Cancer Center, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    2. Department of Genetics, Cell Biology and Development, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    3. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain
    • Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
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    • fax: 612-625-4648


  • Potential conflict of interest: Dr. Llovet consults for and received grants from Bayer and Bristol-Myers Squibb. He also consults for ImClone and Biocompatibles.

  • J. M. L. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK076986-01), the European Comission-FP7 Framework (HEPTROMIC, Proposal No. 259744), The Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (SAF-2010-16055), and the Asociación Española Contra el Cáncer. D. A. L. is supported by grants U01 CA84221 and R01 CA113636 from the National Cancer Institute.

Abstract

Hepatocellular carcinoma (HCC) is one of the deadliest solid cancers and is the third leading cause of cancer-related death. There is a universal estimated male/female ratio of 2.5, but the reason for this is not well understood. The Sleeping Beauty (SB) transposon system was used to elucidate candidate oncogenic drivers of HCC in a forward genetics screening approach. Sex bias occurrence was conserved in our model, with male experimental mice developing liver tumors at reduced latency and higher tumor penetrance. In parallel, we explored sex differences regarding genomic aberrations in 235 HCC patients. Liver cancer candidate genes were identified from both sexes and genotypes. Interestingly, transposon insertions in the epidermal growth factor receptor (Egfr) gene were common in SB-induced liver tumors from male mice (10/10, 100%) but infrequent in female mice (2/9, 22%). Human single-nucleotide polymorphism data confirmed that polysomy of chromosome 7, locus of EGFR, was more frequent in males (26/62, 41%) than females (2/27, 7%) (P = 0.001). Gene expression–based Poly7 subclass patients were predominantly male (9/9) compared with 67% males (55/82) in other HCC subclasses (P = 0.02), and this subclass was accompanied by EGFR overexpression (P < 0.001). Conclusion: Sex bias occurrence of HCC associated with EGFR was confirmed in experimental animals using the SB transposon system in a reverse genetic approach. This study provides evidence for the role of EGFR in sex bias occurrences of liver cancer and as the driver mutational gene in the Poly7 molecular subclass of human HCC. (HEPATOLOGY 2013)

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