Rare CpG island methylator phenotype in ulcerative colitis-associated neoplasias

Gastroenterology. 2007 Apr;132(4):1254-60. doi: 10.1053/j.gastro.2007.01.035. Epub 2007 Jan 25.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Cadherins / genetics
  • Carrier Proteins / genetics
  • Colitis, Ulcerative / complications
  • Colitis, Ulcerative / genetics*
  • Colitis, Ulcerative / metabolism
  • Colonic Neoplasms / etiology
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / 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

Substances

  • 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