Profile of aberrant CpG island methylation along multistep gastric carcinogenesis

Gyeonghoon Kang, Sun Lee, Jung Sun Kim, Hwoon Yong Jung

Research output: Contribution to journalArticleResearchpeer-review

101 Citations (Scopus)

Abstract

The stomach is one of the organs whose epithelial cells frequently undergo aberrant methylation of CpG islands. To date, several reports on the methylation of various genes in gastric cancer (GC) have been published. However, most of these studies have focused on cancer tissues or a single gene only and gave no information about the methylation status of specific genes in the premalignant stages or the concurrent methylation of other genes in specific lesions. We attempted to investigate methylation of multiple genes in a large sample collection of GC (n = 80), gastric adenoma (GA) (n = 79), intestinal metaplasia (IM) (n = 57), and chronic gastritis (CG) (n = 74). We determined the methylation frequency of 12 genes, including APC, COX-2, DAP-kinase, E-cadherin, GSTP1, hMLH1, MGMT, p16, p14, RASSF1A, THBS1, and TIMP3, by methylation-specific PCR. Five different classes of methylation behaviors were found: (a) genes methylated in GC only (GSTP1 and RASSF1A), (b) genes showing low methylation frequency (<12%) in CG, IM, and gastric adenoma (GA) but significantly higher methylation frequency in GC (COX-2, hMLH1, p16), (c) a gene with low and similar methylation frequency (8.8-21.3%) in four-step lesions (MGMT), (d) genes with high and similar methylation frequency (53-85%) in four-step lesions (APC and E-cadherin), and (e) genes showing an increasing tendency with or without fluctuation of the methylation frequency along the progression (DAP-kinase, p14, THBS1, and TIMP-3). The average number of methylated genes was 2.7, 3.6, 3.4, and 5.2 per 12 tested genes in CG, IM, GA, and GC, respectively. Aberrant methylation at multiple loci in the same lesions suggests an overall deregulation of the methylation control, which occurs early in multistep gastric carcinogenesis. Our results suggest that tumor-suppressor genes show a gene-type specific methylation profile along the multistep carcinogenesis and that aberrant CpG island methylation tend to accumulate along the multistep carcinogenesis.

Original languageEnglish
Pages (from-to)519-526
Number of pages8
JournalLaboratory Investigation
Volume83
Issue number4
DOIs
StatePublished - 1 Apr 2003

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CpG Islands
Methylation
Stomach
Carcinogenesis
Genes
Stomach Neoplasms
Metaplasia
Gastritis
Death-Associated Protein Kinases
Adenoma
Cadherins
Tissue Inhibitor of Metalloproteinase-3
APC Genes

Cite this

Kang, Gyeonghoon ; Lee, Sun ; Kim, Jung Sun ; Jung, Hwoon Yong. / Profile of aberrant CpG island methylation along multistep gastric carcinogenesis. In: Laboratory Investigation. 2003 ; Vol. 83, No. 4. pp. 519-526.
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abstract = "The stomach is one of the organs whose epithelial cells frequently undergo aberrant methylation of CpG islands. To date, several reports on the methylation of various genes in gastric cancer (GC) have been published. However, most of these studies have focused on cancer tissues or a single gene only and gave no information about the methylation status of specific genes in the premalignant stages or the concurrent methylation of other genes in specific lesions. We attempted to investigate methylation of multiple genes in a large sample collection of GC (n = 80), gastric adenoma (GA) (n = 79), intestinal metaplasia (IM) (n = 57), and chronic gastritis (CG) (n = 74). We determined the methylation frequency of 12 genes, including APC, COX-2, DAP-kinase, E-cadherin, GSTP1, hMLH1, MGMT, p16, p14, RASSF1A, THBS1, and TIMP3, by methylation-specific PCR. Five different classes of methylation behaviors were found: (a) genes methylated in GC only (GSTP1 and RASSF1A), (b) genes showing low methylation frequency (<12{\%}) in CG, IM, and gastric adenoma (GA) but significantly higher methylation frequency in GC (COX-2, hMLH1, p16), (c) a gene with low and similar methylation frequency (8.8-21.3{\%}) in four-step lesions (MGMT), (d) genes with high and similar methylation frequency (53-85{\%}) in four-step lesions (APC and E-cadherin), and (e) genes showing an increasing tendency with or without fluctuation of the methylation frequency along the progression (DAP-kinase, p14, THBS1, and TIMP-3). The average number of methylated genes was 2.7, 3.6, 3.4, and 5.2 per 12 tested genes in CG, IM, GA, and GC, respectively. Aberrant methylation at multiple loci in the same lesions suggests an overall deregulation of the methylation control, which occurs early in multistep gastric carcinogenesis. Our results suggest that tumor-suppressor genes show a gene-type specific methylation profile along the multistep carcinogenesis and that aberrant CpG island methylation tend to accumulate along the multistep carcinogenesis.",
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Profile of aberrant CpG island methylation along multistep gastric carcinogenesis. / Kang, Gyeonghoon; Lee, Sun; Kim, Jung Sun; Jung, Hwoon Yong.

In: Laboratory Investigation, Vol. 83, No. 4, 01.04.2003, p. 519-526.

Research output: Contribution to journalArticleResearchpeer-review

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