Rare CpG island methylator phenotype in ulcerative colitis-associated neoplasias.

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, ERalpha, 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 ERalpha) 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.

• Authors: Kazuo Konishi, Lanlan Shen, Suna Wang, Stephen J Meltzer, Noam Harpaz, Jean-Pierre J Issa
• Journal: Gastroenterology (Gastroenterology) Vol. 132 Issue 4 Pg. 1254-60 (Apr 2007) ISSN: 0016-5085 [Print] United States
• PMID: 17408633 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• APBA1 protein, human
• APBA2 protein, human
• Adaptor Proteins, Signal Transducing
• Cadherins
• Carrier Proteins
• DNA, Neoplasm
• DNA-Binding Proteins
• Estrogen Receptor alpha
• Intercellular Signaling Peptides and Proteins
• MLH1 protein, human
• Membrane Proteins
• Neoplasm Proteins
• Nerve Tissue Proteins
• Nuclear Proteins
• SFRP1 protein, human
• TMEFF2 protein, human
• Tumor Suppressor Proteins
• L1Hs-encoded protein p40, human
• DNA Modification Methylases
• MGMT protein, human
• MutL Protein Homolog 1
• DNA Repair Enzymes

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adult
• Aged
• Aged, 80 and over
• Cadherins (genetics)
• Carrier Proteins (genetics)
• Colitis, Ulcerative (complications, genetics, metabolism)
• Colonic Neoplasms (etiology, genetics, metabolism)
• CpG Islands (genetics)
• DNA Methylation
• DNA Modification Methylases (genetics)
• DNA Repair
• DNA Repair Enzymes (genetics)
• DNA, Neoplasm (genetics)
• DNA-Binding Proteins (genetics)
• Estrogen Receptor alpha (genetics)
• Female
• Follow-Up Studies
• Friedreich Ataxia
• Genes, p16 (physiology)
• Humans
• Intercellular Signaling Peptides and Proteins (genetics)
• Male
• Membrane Proteins (genetics)
• Middle Aged
• MutL Protein Homolog 1
• Neoplasm Proteins
• Nerve Tissue Proteins (genetics)
• Nuclear Proteins (genetics)
• Phenotype
• Polymerase Chain Reaction
• Tumor Suppressor Proteins (genetics)