The relationship between hypomethylation and CpG island methylation in colorectal neoplasia.
Tumors are often characterized by an imbalance in cytosine methylation as manifested both by hypermethylation of CpG islands and by genome hypomethylation. These epigenetic changes were assessed in colorectal neoplasia to determine whether they arose through a common mechanism or indeed were distinct and unrelated phenomena. Fresh representative samples of adenomas, hyperplastic polyps, colorectal cancers, and normal mucosa were used in this study. Global methylation levels were measured by analyzing the methyl-accepting capacity of DNA. Methylation of p16, hMLH1, and MINT 1, 2, 12, and 31 were assessed by bisulfite polymerase chain reaction. Microsatellite status was determined by polymerase chain reaction using six markers and hMLH1 and proliferating cell nuclear antigen expression was assessed by immunohistochemistry. Normal colonic mucosa had a higher endogenous 5-methyl cytosine content than all proliferative lesions of the colon (P < 0.001). The extent of demethylation in hyperplastic polyps and adenomas was significantly related to its proliferative rate. Right-sided hyperplastic polyps were more likely to be methylated than adenomas (odds ratio, 2.3; confidence interval, 1.1 to 4.6). There was no relationship between the level of global hypomethylation and hypermethylation. Some hyperplastic colorectal polyps have a propensity to develop dense CpG island methylation. Hypermethylation and hypomethylation contribute separately to the process of carcinogenesis.
Bariol
Carolyn
C
Department of Medical Oncology, Saint Vincent's Hospital, Darlinghurst and School of Medicine, University of New South Wales, Sydney, Australia.
Suter
Catherine
C
Cheong
Kay
K
Ku
Su-Lyn
SL
Meagher
Alan
A
Hawkins
Nicholas
N
Ward
Robyn
R
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D002455:Cell Division; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D003111:Colonic Polyps / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology; D012016:Reference Values
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D015226:Dinucleoside Phosphates; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C501486:MLH1 protein, human; C015772:CpG dinucleotide