Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas

Jae Hyuk Lee, Seun Ja Park, Susan C. Abraham, Jae Sung Seo, Jong Hee Nam, Chan Choi, Sang Woo Juhng, Asif Rashid, Stanley R. Hamilton, Tsung Teh Wu

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Gastric carcinogenesis involves multiple genetic and epigenetic alterations. Epigenetic silencing of tumor-related genes due to CpG island methylation (CIM) has been recently reported in gastric cancer, but the role in precursor lesions is not well understood. We analysed the methylation status of the tumor suppressor gene p16, the DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using methylation-specific polymerase chain reaction in 35 polypoid adenomas and 46 flat dysplasias unassociated with carcinoma, 34 early adenocarcinomas (T1N0M0) and associated adenomas/dysplasias, and corresponding adjacent non-neoplastic mucosa. The extent of CIM was defined by the fraction of methylated loci (methylation index), and compared with previously characterized genetic alterations (microsatellite instability (MSI) and APC gene mutation). We found that methylation of p16 was more frequent in adenocarcinoma-associated dysplasias/adenomas (29%) and adenocarcinomas (44%) as compared to flat dysplasias (4%) and adenomas (18%) unassociated with adenocarcinoma (P = 0.001). The mean methylation index increased from normal/chronic gastritis (CG) mucosa (0.09) to intestinal metaplasia (IM) (0.16), flat dysplasias (0.40) or polypoid adenomas (0.41) unassociated with carcinoma, dysplasias/adenomas associated with carcinoma (0.44), and adenocarcinomas (0.44). There was no difference in frequencies of high-level CpG island methylation (CIM-H, methylation index ≥0.5) among flat dysplasias (50%) and polypoid adenomas (51%) unassociated with carcinoma, dysplasias/adenomas associated with adenocarcinoma (47%), and adenocarcinoma (47%). CIM-H was present in 15% of IM, but not in normal/CG mucosa. There was a significant correlation between methylation of hMLH1 and high-level of microsatellite instability (MSI-H): methylation of hMLH1 was present in 71% of MSI-H tumors, but only 8% of MSI-low tumors and 13% of microsatellite-stable tumors (P = 0.0001). There was no statistical difference between methylation index and APC mutation. Our results indicate that concurrent promoter methylation is an early and frequent event in gastric tumorigenesis, including both MSI-H and microsatellite-stable neoplasms. Methylation of the p16 gene may contribute to the malignant transformation of gastric precursor lesions.

Original languageEnglish (US)
Pages (from-to)4646-4654
Number of pages9
JournalOncogene
Volume23
Issue number26
DOIs
StatePublished - Jun 3 2004
Externally publishedYes

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CpG Islands
Methylation
Stomach
Adenocarcinoma
Adenoma
Microsatellite Instability
Carcinoma
Mucous Membrane
Metaplasia
Gastritis
Neoplasms
Epigenomics
Microsatellite Repeats
Carcinogenesis
APC Genes
p16 Genes
Mutation
DNA Mismatch Repair
Tumor Suppressor Genes

Keywords

  • CpG island methylation
  • Gastric neoplasms
  • Precursor lesions

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Lee, J. H., Park, S. J., Abraham, S. C., Seo, J. S., Nam, J. H., Choi, C., ... Wu, T. T. (2004). Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas. Oncogene, 23(26), 4646-4654. https://doi.org/10.1038/sj.onc.1207588

Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas. / Lee, Jae Hyuk; Park, Seun Ja; Abraham, Susan C.; Seo, Jae Sung; Nam, Jong Hee; Choi, Chan; Juhng, Sang Woo; Rashid, Asif; Hamilton, Stanley R.; Wu, Tsung Teh.

In: Oncogene, Vol. 23, No. 26, 03.06.2004, p. 4646-4654.

Research output: Contribution to journalArticle

Lee, JH, Park, SJ, Abraham, SC, Seo, JS, Nam, JH, Choi, C, Juhng, SW, Rashid, A, Hamilton, SR & Wu, TT 2004, 'Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas', Oncogene, vol. 23, no. 26, pp. 4646-4654. https://doi.org/10.1038/sj.onc.1207588
Lee JH, Park SJ, Abraham SC, Seo JS, Nam JH, Choi C et al. Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas. Oncogene. 2004 Jun 3;23(26):4646-4654. https://doi.org/10.1038/sj.onc.1207588
Lee, Jae Hyuk ; Park, Seun Ja ; Abraham, Susan C. ; Seo, Jae Sung ; Nam, Jong Hee ; Choi, Chan ; Juhng, Sang Woo ; Rashid, Asif ; Hamilton, Stanley R. ; Wu, Tsung Teh. / Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas. In: Oncogene. 2004 ; Vol. 23, No. 26. pp. 4646-4654.
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