title: Promoter methylation status of the MGMT, hMLH1, and CDKN2A/p16 genes in non-neoplastic mucosa of patients with and without colorectal adenomas.
abstract: The aberrant methylation of CpG islands is a common epigenetic alteration found in cancers. The process contributes to cancer formation through the transcriptional silencing of tumor suppressor genes. CpG island methylation has been observed in aberrant crypt foci (ACF) and adenomas in the colon, implicating it in the earliest aspects of colon cancer formation. In addition, some investigators have identified an age-related increase in DNA methylation of the ESR1 locus in the colon mucosa, suggesting that DNA methylation may be a pre-neoplastic change that increases the risk of colon adenomas and colon cancer. We investigated the methylation status in the promoter regions of the CDKN2A/p16, hMLH1, and MGMT genes in human non-neoplastic rectal mucosa and evaluated whether these methylation markers may predict the presence of adenomatous polyps in the colon. The promoter methylation patterns of these genes were examined in rectal biopsies (mucosa samples) of 97 colorectal adenoma cases and 94 healthy controls using methylation-specific PCR (MSP) assays. Methylation of the MGMT and hMLH1 genes was present in both cases and controls, with a frequency of 12.4% and 18.1% for the MGMT gene and 12.4% and 11.7% for the hMLH1 gene. The frequency of CDKN2A/p16 promoter methylation was very rare in normal colorectal tissue with a frequency of approximately 2%. Overall, no apparent case-control difference was identified in the methylation status of these genes, either alone or in combination. hMLH1 methylation was more frequently observed among overweight or obese subjects (BMI>/=25) with an adjusted OR of 3.7 (95% CI=1.0-13.7). Methylated alleles of the hMLH1 and MGMT genes were frequently detected in normal rectal mucosa, while the frequency of CDKN2A/p16 methylation detected was very low. The methylation status of these genes in rectal mucosa biopsies detected by MSP assays may not distinguish between patients with and without adenomas in the colon.
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors.forename: Chuanzhong
authors.initials: C
authors.lastname: Ye
authors.forename: Martha J
authors.initials: MJ
authors.lastname: Shrubsole
authors.forename: Qiuyin
authors.initials: Q
authors.lastname: Cai
authors.forename: Reid
authors.initials: R
authors.lastname: Ness
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
authors.forename: Walter
authors.initials: W
authors.lastname: Smalley
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Kay
authors.initials: K
authors.lastname: Washington
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D019942:Genes, p16; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000070957:MutL Protein Homolog 1