Rare CpG island methylator phenotype in ulcerative colitis-associated neoplasias.
OBJECTIVE
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.
Konishi
Kazuo
K
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Shen
Lanlan
L
Wang
Suna
S
Meltzer
Stephen J
SJ
Harpaz
Noam
N
Issa
Jean-Pierre J
JP
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005621:Friedreich Ataxia; D019942:Genes, p16 / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D002352:Carrier Proteins; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C079091:APBA1 protein, human; C491636:APBA2 protein, human; C501486:MLH1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C423567:TMEFF2 protein, human; C077214:L1Hs-encoded protein p40, human; C515491:MGMT protein, human