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Clinical Trial
. 2001 Mar;48(3):367-71.
doi: 10.1136/gut.48.3.367.

Hypermethylation of the promoter region of the E-cadherin gene (CDH1) in sporadic and ulcerative colitis associated colorectal cancer

J M Wheeler  1 , H C Kim, J A Efstathiou, M Ilyas, N J Mortensen, W F Bodmer
Affiliations
Clinical Trial

Hypermethylation of the promoter region of the E-cadherin gene (CDH1) in sporadic and ulcerative colitis associated colorectal cancer

J M Wheeler et al. Gut. 2001 Mar.

Abstract

Background: Ulcerative colitis associated colorectal cancer (UCACRC) has several distinctive clinicopathological and genetic features which differ from sporadic colorectal cancer (SCRC). Hypermethylation of the E-cadherin gene (CDH1) has not been described previously in colorectal cancer.

Aims: A panel of SCRC and UCACRC were investigated for mutations in CDH1, and for hypermethylation of the promoter region of CDH1.

Subjects and methods: DNA was available from 14 patients with UCACRC and from 14 with SCRC. All exons of CDH1 were amplified with the polymerase chain reaction (PCR) and screened using single strand conformational polymorphism and direct sequencing. Hypermethylation of the CDH1 promoter region was determined by methylation specific PCR following bisulphite modification, and compared with E-cadherin protein expression from a previous immunohistochemistry study.

Results: Thirteen of 28 cancers (46%) were hypermethylated in the CDH1 promoter region-eight cancers (57%) in the UCACRC group and five cancers (36%) in the SCRC group (NS)-and this correlated with reduced E-cadherin expression (p<0.05). There was a trend for methylation to be associated with a more advanced stage of cancer although this did not reach statistical significance. There were no mutations in CDH1 in either group although there were several polymorphisms.

Conclusion: We have demonstrated hypermethylation of the promoter region in CDH1 in 46% of colorectal cancers studied. There was no difference between the UCACRC and SCRC groups. Just as there are specific differences in the genetic changes between UCACRC and SCRC, there is also likely to be a large degree of overlap among the genetic pathways of these cancers.

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Figures

Figure 1
Figure 1
Silver staining of methylation specific polymerase chain reaction (PCR) products following electrophoresis on an acrylamide gel. Sample pairs 1-6 are from ulcerative colitis associated colorectal cancer (UCACRC), and 7-11 are from sporadic colorectal cancer (SCRC). E-cadherin protein expression is shown as present (+; grade 2/3) or absent (−; grade 0/1). Primer sets used for PCR amplification are designated as unmethylated (U) or methylated (M), and a PCR product is shown as present (+) or absent (−). A PCR product is seen using unmethylated primers in the unmethylated breast cancer cell line, MDA-MA-468, and with methylated primers in the methylated breast cancer cell line, MDA-MA-435 (C=control). Hypermethylation of the promoter region of CDH1 correlated significantly with reduced E-cadherin immunohistochemical expression (Fisher's exact test, p=0.036). The methylated cancers that expressed E-cadherin protein may have been hemimethylated (methylation of one allele) and were therefore still able to express E-cadherin protein.
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