Article

CpG Island Methylation in Colorectal Adenomas

Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095, USA.
American Journal Of Pathology (Impact Factor: 4.6). 10/2001; 159(3). DOI: 10.1016/S0002-9440(10)61789-0
Source: PubMed Central

ABSTRACT Methylation of cytosines in CpG islands silences gene expression. CpG island methylator phenotype (CIMP) in colorectal cancers is characterized by abnormal methylation of multiple CpG islands including those in several tumor suppressor genes such as p16, hMLH1, and THBS1. CpG island methylation has not been well characterized in adenomas. We evaluated methylation status at p16, MINT2, and MINT31 loci, which are frequently methylated in colorectal carcinomas, in 108 colorectal adenomas from a prospective study of 50 patients without cancer. Methylation at one or more loci was present in 48% (52 of 108) of adenomas with 25% (19 of 76) CIMP-high (two or more methylated loci) and 32% (24 of 76) CIMP-low (one methylated locus). The p16 gene was methylated in 27% (19 of 71) of adenomas. Methylation status of different adenomas from the same patient was not correlated (odds ratio, 0.93; P = 0.77). Adenomas with tubulovillous or villous histology were frequently methylated: 73% (17 of 26) versus 41% (35 of 85) of tubular adenomas (odds ratio, 3.46; P = 0.02). High levels of microsatellite instability were more frequent in adenomas without methylation (13% versus 2%; odds ratio, 8.48; P = 0.05). Our results indicate that methylation plays an important role early in colorectal tumorigenesis. CpG island methylation is more common in adenomas with tubulovillous/villous histology, a characteristic associated with more frequent predisposition to invasive carcinoma. Methylation is distinct from microsatellite instability and develops in individual adenomas rather than resulting from a field defect in an individual patient.

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    • "In fact, there has been no consensus on the definition of CIMP positive yet. Different authors defined tumors that had methylation of two of three [21, 23], three of five [12, 24], three of six [25], or three of seven [2] genes as CIMP positive. The criterion adopted in our study referred to previous studies [2, 12, 26]. "
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    ABSTRACT: Purpose. In the present study, the prognostic significance of CpG island methylator phenotype (CIMP) in stage II/III sporadic colorectal cancer was evaluated using a five-gene panel. Methods. Fifty stage II/III colorectal cancer patients who received radical resection were included in this study. Promoter methylation of p14ARF, hMLH1, p16INK4a, MGMT, and MINT1 was determined by methylation specific polymerase chain reaction (MSP). CIMP positive was defined as hypermethylation of three or more of the five genes. Impact factors on disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier method (log-rank test) and adjusted Cox proportional hazards model. Results. Twenty-four percent (12/50) of patients were characterized as CIMP positive. Univariate analysis showed stage III (P = 0.049) and CIMP positive (P = 0.014) patients who had significantly inferior DFS. In Cox regression analysis, CIMP positive epigenotype was independently related with poor DFS with HR = 2.935 and 95% CI: 1.193-7.220 (P = 0.019). In patients with CIMP positive tumor, those receiving adjuvant chemotherapy had a poor DFS than those without adjuvant chemotherapy (P = 0.023). Conclusions. CIMP positive was significantly correlated with decreased DFS in stage II/III colorectal cancer. Patients with CIMP positive locally advanced sporadic colorectal cancers may not benefit from 5-fluorouracil based adjuvant chemotherapy.
    Gastroenterology Research and Practice 01/2014; 2014:436985. DOI:10.1155/2014/436985 · 1.75 Impact Factor
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    • "DNA methylation effects of a number of mediating genes in CRC development and the significance of the aberrant methylation in CRC have been reported [3,6,7]. The hypermethylation of several promoters including APC, p16INK4a, and TIMP3 in CRC [8,9] and the methylation-induced silencing of cancer suppressor genes were investigated by a quantitative approach [10]. "
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    ABSTRACT: The purpose of this paper was to elucidate the potential methylation levels of adjacent normal and cancer tissues by comparing them with normal colorectal tissues, and to describe the correlations between the methylation and clinical parameters in Korean colorectal cancer (CRC) patients. Hypermethylation profiles of nine genes (RASSF1, APC, p16(INK4a), Twist1, E-cadherin, TIMP3, Smad4, COX2, and ABCB1) were examined with 100 sets of cancer tissues and 14 normal colorectal tissues. We determined the hypermethylation at a given level by a percent of methylation ratio value of 10 using quantitative methylation real-time polymerase chain reaction. Nine genes' hypermethylation levels in Korean CRC patient tissues were increased more higher than normal colorectal tissues. However, the amounts of p16(INK4a) and E-cadherin gene hypermethylation in normal and CRC tissues were not significantly different nor did TIMP3 gene hypermethylation in adjacent normal and cancer tissues differ significantly. The hypermethylation of TIMP3, E-cadherin, ABCB1, and COX2 genes among other genes were abundantly found in normal colorectal tissues. The hypermethylation of nine genes' methylation in cancer tissues was not significantly associated with any clinical parameters. In Cohen's kappa test, it was moderately observed that RASSF1 was related with E-cadherin, and Smad4 with ABCB1 and COX2. This study provides evidence for different hypermethylation patterns of cancer-associated genes in normal and CRC tissues, which may serve as useful information on CRC cancer progression.
    07/2012; 45(4):251-8. DOI:10.3961/jpmph.2012.45.4.251
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    • "Aberrant DNA promoter methylation has previously been shown to be an early event in the development of colorectal cancer [6-10]. Several reports of DNA methylation biomarkers tested in fecal [8,11-15] and blood samples [16-19] suggest the suitability of epigenetic biomarkers in early diagnostics of the disease. "
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    ABSTRACT: The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. This study investigates a panel of epigenetic markers for the detection of colorectal cancer and adenomas. Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the biomarker panel. Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94%) and adenomas (35-91%), whereas normal mucosa samples were rarely (0-5%) methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa. The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.
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