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: 4.59). 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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Available from: Jeffrey S Morris, Aug 28, 2014
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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.
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    • "For genetic events, frequency points to drivers, but for DNA methylation, frequency may point to intrinsic gene susceptibility rather than function/selection (Estecio et al. 2010). Indeed, many of the known tumor-suppressors hypermethylated in cancer and leukemias have methylation frequencies of 10%–30% only in target malignancies (e.g., CDKN2B in AML, CDKN2A in colon cancer and melanoma, VHL in renal cancer, etc.) (Herman et al. 1994;Gonzalgo et al. 1997;Baylin and Herman 2000;Rashid et al. 2001;Raj et al. 2007;Jonsson et al. 2010). It is possible that shared lesions in mouse and human leukemogenesis may point to driver genes, and we identified some potential examples such as PAX3, TLX3, ALK, and GATA2. "
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    ABSTRACT: The Myelodysplastic syndrome (MDS) is a clonal hematologic disorder that frequently evolves to acute myeloid leukemia (AML). Its pathogenesis remains unclear, but mutations in epigenetic modifiers are common and the disease often responds to DNA methylation inhibitors. We analyzed DNA methylation in the bone marrow and spleen in two mouse models of MDS/AML, the NUP98-HOXD13 (NHD13) mouse and the RUNX1 mutant mouse model. Methylation array analysis showed an average of 512/3445 (14.9%) genes hypermethylated in NHD13 MDS and 331 (9.6%) genes hypermethylated in RUNX1 MDS. 32% of genes in common between the two models (2/3 NHD13 mice, and 2/3 RUNX1 mice) were also hypermethylated in at least 2 out of 19 human MDS samples. Detailed analysis of 41 genes in mice showed progressively drift in DNA methylation from young to old normal bone marrow and spleen; to MDS, where we detected accelerated age-related methylation; and finally to AML, which markedly extends DNA methylation abnormalities. Most of these genes showed similar patterns in human MDS and AML. Repeat element hypomethylation was rare in MDS but marked the transition to AML in some cases. Our data show consistency in patterns of aberrant DNA methylation in human and mouse MDS and suggest that epigenetically, MDS displays an accelerated aging phenotype.
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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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