CpG island methylation in colorectal adenomas - PubMed (original) (raw)

CpG island methylation in colorectal adenomas

A Rashid et al. Am J Pathol. 2001 Sep.

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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Figures

Figure 1.

Figure 1.

Methylation analysis of CpG islands in adenomas. Methylation of p16, MINT2, and MINT31 was evaluated by bisulfite-PCR and restriction enzyme digestion by methylation-specific enzymes. Loci examined and adenoma numbers are indicated above each gel. Arrows indicate unmethylated alleles and block arrows indicate methylated alleles. RKO is a colon cancer cell line included as a positive control. Samples 1, 3, and 4 are methylated for p16; sample 1 for MINT31, and samples 2 and 3 for MINT2. Sample 2 shows nonspecific amplification for MINT31 as the other band present after restriction enzyme digest in methylated samples is not present.

Figure 2.

Figure 2.

Frequency of methylation of p16, MINT2, MINT31, and at any locus in adenomas.

Figure 3.

Figure 3.

Frequency of CIMP status in tubular adenomas (TA) and tubulovilluos/villous adenomas (TVA/VA).

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