Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein–Barr virus

Authors

  • Masanobu Kusano M.D.,

    1. First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan
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  • Minoru Toyota M.D., Ph.D.,

    Corresponding author
    1. First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan
    2. Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan
    3. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Japan
    • First Department of Internal Medicine, Sapporo Medical University, South 1,West 16, Chuo-ku, Sapporo 060-8543, Japan
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    • Fax: (011) 81-11-618-3313

  • Hiromu Suzuki M.D., Ph.D.,

    1. First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan
    2. Department of Public Health, Sapporo Medical University, Sapporo, Japan
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  • Kimishige Akino M.D.,

    1. First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan
    2. Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan
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  • Fumio Aoki,

    1. Information Center for Computer Communication, Sapporo Medical University, Sapporo, Japan
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  • Masahiro Fujita M.D., Ph.D.,

    1. Keiyukai Institute of Clinical Pathology, Keiyukai Sapporo Hospital, Sapporo, Japan
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  • Masao Hosokawa M.D.,

    1. Department of Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan
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  • Yasuhisa Shinomura M.D., Ph.D.,

    1. First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan
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  • Kohzoh Imai M.D., Ph.D.,

    1. First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan
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  • Takashi Tokino M.D., Ph.D.

    1. Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan
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Abstract

BACKGROUND

The CpG island methylator phenotype (CIMP), which is characterized by simultaneous methylation of the CpG islands of multiple genes, has been recognized as one of the important mechanisms in gastrointestinal carcinogenesis.

METHODS

Methylation of the 5 methylated-in-tumors (MINT) loci and 12 tumor-related genes in 78 primary gastric carcinomas was examined using combined bisulfite-restriction analysis. Epstein–Barr virus (EBV)-associated gastric tumors were detected using real-time polymerase chain reaction analysis followed by an evaluation of the correlations between CIMP status, EBV-association, and genetic alteration of p53 and K-ras. The authors compared the clinicopathologic features of gastric carcinomas that had high CIMP methylation (CIMP-H) with tumors that had low CIMP methylation (CIMP-L) or negative CIMP methylation (CIMP-N).

RESULTS

The methylation profiles of 12 genes showed nonrandom methylation, supporting the presence of CIMP in gastric carcinoma. No p53 mutations were detected among CIMP-H tumors, and no EBV association was detected in tumors that showed mutation of p53 and K-ras. In a multiple logistic regression model with CIMP-H as the dependent variable, proximal location (P = .011), diffuse type (P = .019), and less advanced pathologic TNM status (P = .043) contributed significantly to CIMP-H. Patients who had CIMP-N gastric tumors had a significantly worse survival than patients who had CIMP-H tumors (P = .004) or CIMP-L tumors (P = .012). EBV-associated tumors were associated strongly with CIMP-H, hypermethylation of tumor-related genes, and no p53 or K-ras mutation.

CONCLUSIONS

CIMP status appeared to be associated with distinct genetic, epigenetic, and clinicopathologic features in gastric carcinomas. The finding that gastric carcinomas arose through different molecular pathways may affect not only tumor characteristics but also patient prognosis. Cancer 2006. © 2006 American Cancer Society.

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