Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers

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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  • 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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  • Jyotsna Reddy,

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

    1. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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  • Ziding Feng,

    1. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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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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  • Masaharu Nomura,

    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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  • Jing Yin,

    1. Deparment of Medicine, Division of Gastroenterology, University of Maryland and Greenebaum Cancer Center, Baltimore, MD, USA
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  • Stephen J. Meltzer,

    1. Deparment of Medicine, Division of Gastroenterology, University of Maryland 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

Aberrant methylation of 5′gene promoter regions associated with gene silencing is an epigenetic phenomenon responsible for silencing of tumor suppressor genes in many cancer types. The aims of our study were to study the role of methylation of a large panel of genes during multistage pathogenesis and to correlate our findings with patient age and other clinico-pathological features. We investigated the aberrant promoter methylation profile of 19 genes in 92 colorectal cancers (CRCs) and corresponding nonmalignant epithelia (NME) (n = 57), and selected 15 genes for studying 26 colorectal adenomas (CAs). On the Basis of our results, the genes could be divided into 3 groups. Group 1 consisted of 13 genes whose methylation was tumor-specific. For 8 of these genes, the methylation frequencies in CAs were similar to those of CRCs, but significantly different from the frequencies in NME. Group 2, consisting of 2 genes demonstrating little or no methylation, were present in any sample type. In Group 3, consisting of 4 genes, relatively frequent methylation was present in both CRCs and NME, and the differences between these specimen types were not significant. Methylation of Group 1 genes were tightly correlated with each other, and these genes demonstrated increased methylation frequencies in CRCs with increasing age. Methylation was not correlated with other clinico-pathological features. In general, methylation frequencies of CAs were intermediate between CRCs and NME. Our study constitutes the most comprehensive methylation profile of CRCs, demonstrates that methylation commences early during CRC pathogenesis and is an age-related phenomenon. © 2005 Wiley-Liss, Inc.

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