Aging and DNA methylation in colorectal mucose and cancer

DNA methylation of promoter-associated CpG islands may function as an alter nate mechanism of silencing tumor suppressor genes in multiple neoplasias i ncluding colorectal cancer. De novo methylation of genes appears to be an e arly and frequent event in most neoplasias, For the ER and IGF2 genes, we h ave previously shown that methylation actually begins in the normal colon m ucosa as an age-related event and progresses to hypermethylation in cancer. In this study, we have determined the frequency of age-related methylation in normal colonic mucosa among the genes hypermethylated in colorectal can cer. We studied six genes, including N33, MYOD, p16, HIC-1, THBS1, and CALC A, The N33 gene showed partial methylation in normal colon mucosa, which wa s age-related (r = 0.7; P = 0.003 using regression analysis). Adenomas and cancers showed further hypermethylation at this locus. Similarly, the MYOD gene showed age-related methylation in normal colon mucosa (r = 0.7; P < 0. 00001 using regression analysis) and hypermethylation in cancers. Age-relat ed methylation seems to be gene specific, because p16, THBS1, HIC-1, and CA LCA were not affected. Furthermore, this process may also be modulated by t issue-specific factors. Our study suggests that aging is a major contributi ng factor to hypermethylation in cancer.