Aberrant methylation of Reprimo in human malignancies

Authors

  • Takao Takahashi,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Surgery, Gifu University School of Medicine, Gifu, Japan
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  • Makoto Suzuki,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Hisayuki Shigematsu,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Narayan Shivapurkar,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Chinyere Echebiri,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Masaharu Nomura,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Victor Stastny,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Meena Augustus,

    1. Avalon Pharmaceuticals, Germantown, MD, USA
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  • Chew-Wun Wu,

    1. Department of Surgery, Veterans General Hospital-Taipei, Taipei, Taiwan
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  • Ignacio I. Wistuba,

    1. Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
    2. Department of Anatomic Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile
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  • Stephen J. Meltzer,

    1. Department of Medicine, Division of Gastroenterology, University of Maryland School of Medicine and Greenebaum Cancer Center, Baltimore, MD, USA
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  • Adi F. Gazdar

    Corresponding author
    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    • Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Tx 75390-8593, USA
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    • Fax: +214-648-4940


Abstract

Reprimo is a new candidate mediator of p53-mediated cell cycle arrest at the G2 phase. Loss of Reprimo gene expression accompanied by its promoter methylation was identified in pancreatic and lung cancers. Our aim was to examine the methylation status of Reprimo in a broad range of cancers. We examined Reprimo expression by RT-PCR and the DNA methylation status of the Reprimo promoter by MSP in 39 tumor cell lines. Loss or downregulation of Reprimo expression was frequent (62%), and we confirmed that transcriptional repression of Reprimo was caused by hypermethylation (overall concordance 92%). Treatment of expression-negative cells with 5-aza-2′-deoxycytidine restored Reprimo expression. We then examined aberrant methylation of Reprimo in 645 tumors representing 16 tumor types. Promoter methylation of Reprimo was found in 79% of gastric cancers, 62% of gallbladder cancers, 57% of lymphomas, 56% of colorectal cancers, 40% of esophageal adenocarcinomas, 37% of breast cancers and 31% of leukemias. Methylation frequencies in ovarian cancers, bladder cancers, cervical cancers, brain tumors, malignant mesotheliomas and pediatric tumors were lower (0–20%). Reprimo methylation was rarely detected in nonmalignant tissues (0–11%) except for gastric epithelia. While colorectal polyps were also frequently methylated (27%), chronic cholecystitis samples were infrequently methylated (4%). Furthermore, we failed to identify Reprimo mutation in colorectal and gastric cancer cell lines and 50 primary colorectal cancers. Aberrant methylation of Reprimo with loss of expression is a common event and may contribute to the pathogenesis of some types of human malignancy. © 2005 Wiley-Liss, Inc.

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