CpG Island M`ethylation Status in Gastric Carcinoma with and without Infection of Epstein-Barr Virus

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  • Moon-Sung Chang
    1Department of Pathology, Graduate School of Medicine and
  • Hiroshi Uozaki
    1Department of Pathology, Graduate School of Medicine and
  • Ja-Mun Chong
    1Department of Pathology, Graduate School of Medicine and
  • Tetsuo Ushiku
    1Department of Pathology, Graduate School of Medicine and
  • Kazuya Sakuma
    4Department of Surgery, Jichi Medical School, Tochigi and
  • Shunpei Ishikawa
    2Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo;
  • Rumi Hino
    1Department of Pathology, Graduate School of Medicine and
  • Rita Rani Barua
    1Department of Pathology, Graduate School of Medicine and
  • Yoshiaki Iwasaki
    5Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
  • Kuniyoshi Arai
    5Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
  • Hideki Fujii
    3Department of Surgery, University of Yamanashi, Yamanashi;
  • Hideo Nagai
    4Department of Surgery, Jichi Medical School, Tochigi and
  • Masashi Fukayama
    1Department of Pathology, Graduate School of Medicine and

書誌事項

公開日
2006-05-15
DOI
  • 10.1158/1078-0432.ccr-05-1601
公開者
American Association for Cancer Research (AACR)

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説明

<jats:title>Abstract</jats:title><jats:p>Purpose: EBV-associated gastric carcinoma shows global CpG island methylation of the promoter region of various cancer-related genes. To further clarify the significance of CpG island methylator phenotype (CIMP) status in gastric carcinoma, we investigated methylation profile and clinicopathologic features including overall survival in four subgroups defined by EBV infection and CIMP status: EBV-associated gastric carcinoma and EBV-negative/CIMP-high (H), EBV-intermediate (I), and EBV-negative (N) gastric carcinoma.</jats:p><jats:p>Experimental Design: Methylation-specific PCR was applied to 106 gastric carcinoma cases. CIMP-N, CIMP-I, and CIMP-H status was determined by the number (0, 1-3, and 4-5, respectively) of methylated marker genes (LOX, HRASLS, FLNc, HAND1, and TM), that were newly identified as highly methylated in gastric cancer cell lines. The methylation status of 10 other cancer-related genes (p14, p15, p16, p73, TIMP-3, E-cadherin, DAPK, GSTP1, hMLH1, and MGMT) was also evaluated.</jats:p><jats:p>Results: Nearly all (14 of 15) of EBV-associated gastric carcinoma exhibited CIMP-H, constituting a homogenous group (14%). EBV-negative gastric carcinoma consisted of CIMP-H (24%), CIMP-I (38%), and CIMP-N (24%). EBV-associated gastric carcinoma showed significantly higher frequencies of methylation of cancer-related genes (mean number ± SD = 6.9 ± 1.5) even if compared with EBV-negative/CIMP-H gastric carcinoma (3.5 ± 1.8). Among EBV-negative gastric carcinoma subgroups, CIMP-H gastric carcinoma showed comparatively higher frequency of methylation than CIMP-I or CIMP-N, especially of p16 and hMLH1. CIMP-N gastric carcinoma predominantly consisted of advanced carcinoma with significantly higher frequency of lymph node metastasis. The prognosis of the patients of CIMP-N was significantly worse compared with other groups overall by univariate analysis (P = 0.0313).</jats:p><jats:p>Conclusion: The methylation profile of five representative genes is useful to stratify gastric carcinomas into biologically different subgroups. EBV-associated gastric carcinoma showed global CpG island methylation, comprising a pathogenetically distinct subgroup in CIMP-H gastric carcinoma.</jats:p>

収録刊行物

  • Clinical Cancer Research

    Clinical Cancer Research 12 (10), 2995-3002, 2006-05-15

    American Association for Cancer Research (AACR)

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