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Viral Status Predicts the Patterns of Genome Methylation and Decitabine Response in Merkel Cell Carcinoma

  • Author Footnotes
    10 These authors contributed equally to this work.
    Paul W. Harms
    Footnotes
    10 These authors contributed equally to this work.
    Affiliations
    Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA

    Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
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  • Author Footnotes
    10 These authors contributed equally to this work.
    Monique E. Verhaegen
    Footnotes
    10 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
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  • Josh N. Vo
    Affiliations
    Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA
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  • Jean C. Tien
    Affiliations
    Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA
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  • Drew Pratt
    Affiliations
    Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
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  • Fengyun Su
    Affiliations
    Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA
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  • Saravana M. Dhanasekaran
    Affiliations
    Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA
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  • Xuhong Cao
    Affiliations
    Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA
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  • Doris Mangelberger
    Affiliations
    Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
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  • Julia VanGoor
    Affiliations
    College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, USA
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  • Jae Eun Choi
    Affiliations
    Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA
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  • Vincent T. Ma
    Affiliations
    Division of Hematology and Oncology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
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  • Andrzej A. Dlugosz
    Affiliations
    Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA

    Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Department of Cell & Developmental Biology, Medical School, University of Michigan, Ann Arbor, Michigan, USA
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  • Arul M. Chinnaiyan
    Correspondence
    Correspondence: Arul M. Chinnaiyan, Howard Hughes Medical Institute, Rogel Cancer Center, University of Michigan, 1400 East Medical Center Drive 5316 CCGC, Ann Arbor, Michigan 48109-0602, USA.
    Affiliations
    Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA

    Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA

    Department of Urology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
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  • Author Footnotes
    10 These authors contributed equally to this work.
Published:August 29, 2021DOI:https://doi.org/10.1016/j.jid.2021.07.173
      Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that is classified as Merkel cell polyomavirus-positive (virus positive [VP]) or Merkel cell polyomavirus-negative (virus negative [VN]). Epigenetic changes, such as DNA methylation, can alter gene expression and influence cancer progression. However, patterns of DNA methylation and the therapeutic efficacy of hypomethylating agents have not been fully explored in MCC. We characterized genome-wide DNA methylation in 16 MCC cell lines from both molecular subclasses in comparison with other cancer types and found that the overall profile of MCC is similar to that of small-cell lung carcinoma. Comparison of VP MCC with VN MCC revealed 2,260 differentially methylated positions. The hypomethylating agent decitabine upregulated the expression of antigen-presenting machinery in MCC cell lines and stimulated membrane expression of HLA-A in VP and VN MCC xenograft tumors. Decitabine also induced prominent caspase- and large T antigen‒independent cell death in VP MCC, whereas VN MCC cell lines displayed decreased proliferation without increased cell death. In mouse xenografts, decitabine significantly decreased the size of VP tumors but not that of VN tumors. Our findings indicate that viral status predicts genomic methylation patterns in MCC and that decitabine may be therapeutically effective against MCC through antiproliferative effects, cell death, and increased immune recognition.

      Abbreviations:

      DAC (decitabine), IC50 (half-maximal inhibitory concentration), LT (large T), MCC (Merkel cell carcinoma), MCPyV (Merkel cell polyomavirus), SCLC (small-cell lung carcinoma), VN (virus negative), VP (virus positive)
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