Gastroenterology

Gastroenterology

Volume 132, Issue 4, April 2007, Pages 1254-1260
Gastroenterology

Clinical–alimentary tract
Rare CpG Island Methylator Phenotype in Ulcerative Colitis–Associated Neoplasias

https://doi.org/10.1053/j.gastro.2007.01.035Get rights and content

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.

Section snippets

Patient Samples

We examined a total of 69 primary neoplasias (48 cancers and 21 dysplasias) from 65 patients with UC. All tissue specimens were obtained from patients with UC undergoing surgery at the Mount Sinai Medical Center. The dates of tissue sample acquisition for cancers were similar to those for dysplasias. A series of 69 S-CRCs from 69 patients undergoing surgery at the Johns Hopkins Hospital (n = 31) and the MD Anderson Cancer Center (n = 38) were used as controls. Forty-six samples of colonic

Clinicopathologic Characteristics of Patients

Table 1 shows the clinicopathologic characteristics of studied patients with UC-associated dysplasias (UC-Ds), UC-associated cancers (UC-Cs), and S-CRCs. There was no significant difference in any clinicopathologic characteristics except patient age between UC-Ds or S-CRCs and UC-Cs. Patients with UC-Cs and UC-Ds were significantly younger than those with S-CRCs (age: 50.6 y in UC-Ds and 53.3 y in UC-Cs vs 68.1 y in S-CRC, P = .001 and P < .001, respectively).

Methylation Status in UC-C and S-CRC

The methylation status of 10 genes

Discussion

Previous reports have suggested that epigenetic alterations in UC-associated neoplasias are different from those in sporadic colorectal neoplasias.37, 38, 39, 40 However, this issue remains controversial and different methodology may have contributed to the discrepant results obtained. Here, using a quantitative methylation analysis method, we clearly show that UC-Ds have a high degree of age-related methylation abnormalities as previously reported, but unexpectedly also show that UC-Cs have

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    Supported in part by National Institutes of Health grants CA098006 and CA105346 (to J.P.J. Issa) and CA95323 and CA77057 (to S.J. Meltzer).

    1

    Dr Meltzer’s current affiliation is Gastroenterology Division, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD

    2

    Dr Konishi’s current affiliation is Second Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.

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