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The topography of DNA methylation in the non-neoplastic colonic mucosa surrounding colorectal cancers

Authors

  • Manish Mani Subramaniam,

    1. Department of Pathology, National University Health System, National University of Singapore, Singapore, Singapore
    2. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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  • Marie Loh,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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  • Jason Yongsheng Chan,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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  • Natalia Liem,

    1. Department of Hematology-Oncology, National University Health System, National University of Singapore, Singapore, Singapore
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  • Pei Li Lim,

    1. Department of Hematology-Oncology, National University Health System, National University of Singapore, Singapore, Singapore
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  • Yong Wei Peng,

    1. Department of Hematology-Oncology, National University Health System, National University of Singapore, Singapore, Singapore
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  • Xn Yii Lim,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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  • Khay Guan Yeoh,

    1. Department of Medicine, National University Health System, National University of Singapore, Singapore, Singapore
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  • Barry Iacopetta,

    1. School of Surgery, University of Western Australia, Perth, Australia
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  • Richie Soong,

    1. Department of Pathology, National University Health System, National University of Singapore, Singapore, Singapore
    2. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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  • Manuel Salto-Tellez

    Corresponding author
    1. Department of Pathology, National University Health System, National University of Singapore, Singapore, Singapore
    2. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
    3. Center for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK
    • Clinical Professor (Cons) (JA), Center for Cancer Research and Cell Biology (CCRB), Block 5 Health Sciences. Room Number 01.003, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK.

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  • Manish Mani Subramaniam and Marie Loh contributed equally to the work.
  • There is no potential conflicts of interest.

Abstract

The degree of gene hypermethylation in non-neoplastic colonic mucosa (NNCM) is a potentially important event in the development of colorectal cancer (CRC), particularly for the subgroup with a CpG island methylator phenotype (CIMP). In this study, we aimed to use an unbiased and high-throughput approach to evaluate the topography of DNA methylation in the non-neoplastic colonic mucosa (NNCM) surrounding colorectal cancer (CRC). A total of 61 tissue samples comprising 53 NNCM and 8 tumor samples were obtained from hemicolectomy specimens of two CRC patients (Cases 1 and 2). NNCM was stripped from the underlying colonic wall and samples taken at varying distances from the tumor. The level of DNA methylation in NNCM and tumor tissues was assessed at 1,505 CpG sites in 807 cancer-related genes using Illumina GoldenGate® methylation arrays. Case 1 tumor showed significantly higher levels of methylation compared to surrounding NNCM samples (P < 0.001). The average level of methylation in NNCM decreased with increasing distance from the tumor (r = −0.418; P = 0.017), however this was not continuous and “patches” with higher levels of methylation were observed. Case 2 tumor was less methylated than Case 1 tumor (average β-value 0.181 vs. 0.415) and no significant difference in the level of methylation was observed in comparison to the surrounding NNCM. No evidence was found for a diminishing gradient of methylation in the NNCM surrounding CRC with a high level of methylation. Further work is required to determine whether CIMP+ CRC develop from within “patches” of NCCM that display high levels of methylation. © 2012 Wiley Periodicals, Inc.

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