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CpG island hypermethylator phenotype in gastric carcinoma and its clinicopathological features

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Abstract

Gastric carcinoma (GC) is one of the human cancers in which promoter CpG island hypermethylation is frequently found. CpG island methylator phenotype (CIMP) refers to a subset of GCs which harbor concordant methylation of multiple promoter CpG island loci. However, little is known regarding clinicopathological features of CIMP-positive (CIMP-high) GC. Our study aimed to characterize clinicopathological features of CIMP-high GC. We analyzed 196 cases of GCs for their methylation status in 16 cancer-specific CpG island loci using MethyLight assay and arbitrarily defined CIMP-high GC as those with methylation at 13 or more CpG island loci. With exclusion of microsatellite instability-positive GC and EBV-positive GC from the analysis, CIMP-high GC (n = 10, 6.7%) demonstrated tendency toward higher cancer stage, infiltrative growth type, poor differentiation, and diffuse or mixed type of Lauren classification. CIMP-high GC showed significantly shortened survival compared with that of CIMP-negative GC. When CIMP-negative GC (methylation at 12 or less) was divided into CIMP-intermediate and CIMP-low (methylation at one or none), CIMP-low exhibited better clinical outcome than CIMP-intermediate. Hypermethylation at 14 CpG island loci or more was closely associated with poor clinical outcome and found to be an independent prognostic factor. Our findings that CIMP-high GCs were featured with characteristic clinicopathological parameters, including poor prognosis are distinct from previous studies. More extensive, large-scaled study is necessary to validate the findings of the present study.

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References

  1. Toyota M, Ahuja N, Ohe-Toyota M et al (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96:8681–8686

    Article  CAS  PubMed  Google Scholar 

  2. Weisenberger DJ, Siegmund KD, Campan M et al (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787–793

    Article  CAS  PubMed  Google Scholar 

  3. Ogino S, Goel A (2008) Molecular classification and correlates in colorectal cancer. J Mol Diagn 10:13–27

    Article  CAS  PubMed  Google Scholar 

  4. Kim JH, Shin SH, Kwon HJ, Cho NY, Kang GH (2009) Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers. Virchows Arch 455:485–494

    Article  CAS  PubMed  Google Scholar 

  5. Toyota M, Ahuja N, Suzuki H et al (1999) Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res 59:5438–5442

    CAS  PubMed  Google Scholar 

  6. Enomoto S, Maekita T, Tsukamoto T et al (2007) Lack of association between CpG island methylator phenotype in human gastric cancers and methylation in their background non-cancerous gastric mucosae. Cancer Sci 98:1853–1861

    Article  CAS  PubMed  Google Scholar 

  7. Kang GH, Lee S, Kim WH et al (2002) Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am J Pathol 160:787–794

    CAS  PubMed  Google Scholar 

  8. Chang MS, Uozaki H, Chong JM et al (2006) CpG island methylation status in gastric carcinoma with and without infection of Epstein-Barr virus. Clin Cancer Res 12:2995–3002

    Article  CAS  PubMed  Google Scholar 

  9. Oue N, Oshimo Y, Nakayama H et al (2003) DNA methylation of multiple genes in gastric carcinoma: association with histological type and CpG island methylator phenotype. Cancer Sci 94:901–905

    Article  CAS  PubMed  Google Scholar 

  10. An C, Choi IS, Yao JC et al (2005) Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma. Clin Cancer Res 11:656–663

    CAS  PubMed  Google Scholar 

  11. Kusano M, Toyota M, Suzuki H et al (2006) Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus. Cancer 106:1467–1479

    Article  CAS  PubMed  Google Scholar 

  12. Chan AO, Peng JZ, Lam SK et al (2006) Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation. Gut 55:463–468

    Article  CAS  PubMed  Google Scholar 

  13. Chan AO, Lam SK, Wong BC et al (2003) Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer. Gut 52:502–506

    Article  CAS  PubMed  Google Scholar 

  14. Boland CR, Thibodeau SN, Hamilton SR et al (1998) A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257

    CAS  PubMed  Google Scholar 

  15. Kang GH, Lee S, Cho NY et al (2008) DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest 88:161–170

    Article  CAS  PubMed  Google Scholar 

  16. Yoo EJ, Park SY, Cho NY et al (2008) Helicobacter pylori-infection-associated CpG island hypermethylation in the stomach and its possible association with polycomb repressive marks. Virchows Arch 452:515–524

    Article  CAS  PubMed  Google Scholar 

  17. Park SY, Yoo EJ, Cho NY, Kim N, Kang GH (2009) Comparison of CpG island hypermethylation and repetitive DNA hypomethylation in premalignant stages of gastric cancer, stratified for Helicobacter pylori infection. J Pathol 219:410–416

    Article  CAS  PubMed  Google Scholar 

  18. Park SY, Kook MC, Kim YW et al (2010) Mixed-type gastric cancer and its association with high-frequency CpG island hypermethylation. Virchows Arch 456(6):625–633

    Article  CAS  PubMed  Google Scholar 

  19. Ogino S, Cantor M, Kawasaki T et al (2006) CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut 55:1000–1006

    Article  CAS  PubMed  Google Scholar 

  20. Ogino S, Kawasaki T, Brahmandam M et al (2006) Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis. J Mol Diagn 8:209–217

    Article  CAS  PubMed  Google Scholar 

  21. Goel A, Nagasaka T, Arnold CN et al (2007) The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology 132:127–138

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

Supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A091081).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology, National Cancer Center, Goyang, Gyeonggi-do, South Korea

    Seog-Yun Park & Myeong Cherl Kook

  2. Department of General Surgery, National Cancer Center, Goyang, Gyeonggi-do, South Korea

    Young Woo Kim

  3. Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Nam-Yun Cho, Namhee Jung & Gyeong Hoon Kang

  4. Department of Pathology, 2nd Stage Brain Korea Project and Seoul National University College of Medicine, Seoul, South Korea

    Hyeong-Ju Kwon & Gyeong Hoon Kang

  5. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Tae-You Kim

  6. Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, South Korea

    Gyeong Hoon Kang

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  1. Seog-Yun Park
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  2. Myeong Cherl Kook
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  3. Young Woo Kim
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  5. Namhee Jung
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Correspondence to Gyeong Hoon Kang.

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Park, SY., Kook, M.C., Kim, Y.W. et al. CpG island hypermethylator phenotype in gastric carcinoma and its clinicopathological features. Virchows Arch 457, 415–422 (2010). https://doi.org/10.1007/s00428-010-0962-0

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  • DOI: https://doi.org/10.1007/s00428-010-0962-0

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