The relationship between hypomethylation and CpG island methylation in colorectal neoplasia

Am J Pathol. 2003 Apr;162(4):1361-71. doi: 10.1016/S0002-9440(10)63932-6.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Aged
  • Base Pair Mismatch
  • Carrier Proteins
  • Cell Division
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • Colonic Polyps / genetics
  • Colonic Polyps / pathology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA Methylation*
  • DNA, Neoplasm / genetics*
  • Dinucleoside Phosphates / metabolism*
  • Female
  • Humans
  • Male
  • Middle Aged
  • MutL Protein Homolog 1
  • Neoplasm Proteins / genetics
  • Nuclear Proteins
  • Rectal Neoplasms / genetics*
  • Rectal Neoplasms / pathology
  • Reference Values


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA, Neoplasm
  • Dinucleoside Phosphates
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • cytidylyl-3'-5'-guanosine
  • MutL Protein Homolog 1