Rare CpG Island Methylator Phenotype in Ulcerative Colitis-Associated Neoplasias

Kazuo Konishi, Lanlan Shen, Suna Wang, Stephen Meltzer, Noam Harpaz, Jean Pierre J Issa

Research output: Contribution to journalArticle

Abstract

Background & Aims: We previously reported that a high degree of age-related methylation was found in both the dysplastic and nondysplastic mucosa of patients with ulcerative colitis (UC). Whether this translates into hypermethylation in UC-associated cancers (UC-Cs) is not known. Methods: We evaluated the methylation status of 11 genes (MINT1, 2, 31, hMLH1, p16, p14, MGMT, HPP1, SFRP1, ERα, and LINE-1) in 48 UC-Cs, 21 UC-associated dysplasias, and 69 sporadic colorectal cancers (S-CRCs) using a quantitative bisulfite pyrosequencing analysis. Results: Methylation levels in UC-Cs were lower than S-CRCs for all the genes except MGMT. A methylation index based on the average of Z-scores, for type C (cancer-specific genes: MINT1, MINT2, MINT31, hMLH1, p16, and p14) was -.97 in UC-Cs and .92 in S-CRCs (P = .009). That of type A (age-related genes: HPP1, SFRP1, and ERα) was -1.97 in UC-Cs and 1.24 in S-CRCs (P <.001). We observed a significant difference in the incidence of CpG island methylator phenotype between UC-Cs and S-CRCs (8 of 48 [17%] and 26 of 69 [38%]; P = .022). UC-associated dysplasias had significantly higher methylation of type A gene than UC-Cs (Z-score: .07 and -1.97, respectively; P <.001). By contrast, global DNA methylation measured using a LINE-1 assay was significantly higher in UC-Cs than in S-CRCs (58.2% vs 51.0%, P <.001). Conclusions: DNA methylation alterations are uncommon in UC cancers. Given that both genetic and epigenetic changes are common in UC mucosa and dysplasias, we speculate that the genetic changes lead to a more aggressive clinical course than epigenetic changes.

Original languageEnglish (US)
Pages (from-to)1254-1260
Number of pages7
JournalGastroenterology
Volume132
Issue number4
DOIs
StatePublished - Apr 2007
Externally publishedYes

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CpG Islands
Ulcerative Colitis
Phenotype
Neoplasms
Colorectal Neoplasms
Methylation
Neoplasm Genes
DNA Methylation
Epigenomics
Mucous Membrane
Genes

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Rare CpG Island Methylator Phenotype in Ulcerative Colitis-Associated Neoplasias. / Konishi, Kazuo; Shen, Lanlan; Wang, Suna; Meltzer, Stephen; Harpaz, Noam; Issa, Jean Pierre J.

In: Gastroenterology, Vol. 132, No. 4, 04.2007, p. 1254-1260.

Research output: Contribution to journalArticle

Konishi, Kazuo ; Shen, Lanlan ; Wang, Suna ; Meltzer, Stephen ; Harpaz, Noam ; Issa, Jean Pierre J. / Rare CpG Island Methylator Phenotype in Ulcerative Colitis-Associated Neoplasias. In: Gastroenterology. 2007 ; Vol. 132, No. 4. pp. 1254-1260.
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abstract = "Background & Aims: We previously reported that a high degree of age-related methylation was found in both the dysplastic and nondysplastic mucosa of patients with ulcerative colitis (UC). Whether this translates into hypermethylation in UC-associated cancers (UC-Cs) is not known. Methods: We evaluated the methylation status of 11 genes (MINT1, 2, 31, hMLH1, p16, p14, MGMT, HPP1, SFRP1, ERα, and LINE-1) in 48 UC-Cs, 21 UC-associated dysplasias, and 69 sporadic colorectal cancers (S-CRCs) using a quantitative bisulfite pyrosequencing analysis. Results: Methylation levels in UC-Cs were lower than S-CRCs for all the genes except MGMT. A methylation index based on the average of Z-scores, for type C (cancer-specific genes: MINT1, MINT2, MINT31, hMLH1, p16, and p14) was -.97 in UC-Cs and .92 in S-CRCs (P = .009). That of type A (age-related genes: HPP1, SFRP1, and ERα) was -1.97 in UC-Cs and 1.24 in S-CRCs (P <.001). We observed a significant difference in the incidence of CpG island methylator phenotype between UC-Cs and S-CRCs (8 of 48 [17{\%}] and 26 of 69 [38{\%}]; P = .022). UC-associated dysplasias had significantly higher methylation of type A gene than UC-Cs (Z-score: .07 and -1.97, respectively; P <.001). By contrast, global DNA methylation measured using a LINE-1 assay was significantly higher in UC-Cs than in S-CRCs (58.2{\%} vs 51.0{\%}, P <.001). Conclusions: DNA methylation alterations are uncommon in UC cancers. Given that both genetic and epigenetic changes are common in UC mucosa and dysplasias, we speculate that the genetic changes lead to a more aggressive clinical course than epigenetic changes.",
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AU - Konishi, Kazuo

AU - Shen, Lanlan

AU - Wang, Suna

AU - Meltzer, Stephen

AU - Harpaz, Noam

AU - Issa, Jean Pierre J

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N2 - Background & Aims: We previously reported that a high degree of age-related methylation was found in both the dysplastic and nondysplastic mucosa of patients with ulcerative colitis (UC). Whether this translates into hypermethylation in UC-associated cancers (UC-Cs) is not known. Methods: We evaluated the methylation status of 11 genes (MINT1, 2, 31, hMLH1, p16, p14, MGMT, HPP1, SFRP1, ERα, and LINE-1) in 48 UC-Cs, 21 UC-associated dysplasias, and 69 sporadic colorectal cancers (S-CRCs) using a quantitative bisulfite pyrosequencing analysis. Results: Methylation levels in UC-Cs were lower than S-CRCs for all the genes except MGMT. A methylation index based on the average of Z-scores, for type C (cancer-specific genes: MINT1, MINT2, MINT31, hMLH1, p16, and p14) was -.97 in UC-Cs and .92 in S-CRCs (P = .009). That of type A (age-related genes: HPP1, SFRP1, and ERα) was -1.97 in UC-Cs and 1.24 in S-CRCs (P <.001). We observed a significant difference in the incidence of CpG island methylator phenotype between UC-Cs and S-CRCs (8 of 48 [17%] and 26 of 69 [38%]; P = .022). UC-associated dysplasias had significantly higher methylation of type A gene than UC-Cs (Z-score: .07 and -1.97, respectively; P <.001). By contrast, global DNA methylation measured using a LINE-1 assay was significantly higher in UC-Cs than in S-CRCs (58.2% vs 51.0%, P <.001). Conclusions: DNA methylation alterations are uncommon in UC cancers. Given that both genetic and epigenetic changes are common in UC mucosa and dysplasias, we speculate that the genetic changes lead to a more aggressive clinical course than epigenetic changes.

AB - Background & Aims: We previously reported that a high degree of age-related methylation was found in both the dysplastic and nondysplastic mucosa of patients with ulcerative colitis (UC). Whether this translates into hypermethylation in UC-associated cancers (UC-Cs) is not known. Methods: We evaluated the methylation status of 11 genes (MINT1, 2, 31, hMLH1, p16, p14, MGMT, HPP1, SFRP1, ERα, and LINE-1) in 48 UC-Cs, 21 UC-associated dysplasias, and 69 sporadic colorectal cancers (S-CRCs) using a quantitative bisulfite pyrosequencing analysis. Results: Methylation levels in UC-Cs were lower than S-CRCs for all the genes except MGMT. A methylation index based on the average of Z-scores, for type C (cancer-specific genes: MINT1, MINT2, MINT31, hMLH1, p16, and p14) was -.97 in UC-Cs and .92 in S-CRCs (P = .009). That of type A (age-related genes: HPP1, SFRP1, and ERα) was -1.97 in UC-Cs and 1.24 in S-CRCs (P <.001). We observed a significant difference in the incidence of CpG island methylator phenotype between UC-Cs and S-CRCs (8 of 48 [17%] and 26 of 69 [38%]; P = .022). UC-associated dysplasias had significantly higher methylation of type A gene than UC-Cs (Z-score: .07 and -1.97, respectively; P <.001). By contrast, global DNA methylation measured using a LINE-1 assay was significantly higher in UC-Cs than in S-CRCs (58.2% vs 51.0%, P <.001). Conclusions: DNA methylation alterations are uncommon in UC cancers. Given that both genetic and epigenetic changes are common in UC mucosa and dysplasias, we speculate that the genetic changes lead to a more aggressive clinical course than epigenetic changes.

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