CpG island methylator phenotype in colorectal cancer

M Toyota, N Ahuja, M Ohe-Toyota… - Proceedings of the …, 1999 - National Acad Sciences
M Toyota, N Ahuja, M Ohe-Toyota, JG Herman, SB Baylin, JPJ Issa
Proceedings of the National Academy of Sciences, 1999National Acad Sciences
Aberrant methylation of promoter region CpG islands is associated with transcriptional
inactivation of tumor-suppressor genes in neoplasia. To understand global patterns of CpG
island methylation in colorectal cancer, we have used a recently developed technique called
methylated CpG island amplification to examine 30 newly cloned differentially methylated
DNA sequences. Of these 30 clones, 19 (63%) were progressively methylated in an age-
dependent manner in normal colon, 7 (23%) were methylated in a cancer-specific manner …
Aberrant methylation of promoter region CpG islands is associated with transcriptional inactivation of tumor-suppressor genes in neoplasia. To understand global patterns of CpG island methylation in colorectal cancer, we have used a recently developed technique called methylated CpG island amplification to examine 30 newly cloned differentially methylated DNA sequences. Of these 30 clones, 19 (63%) were progressively methylated in an age-dependent manner in normal colon, 7 (23%) were methylated in a cancer-specific manner, and 4 (13%) were methylated only in cell lines. Thus, a majority of CpG islands methylated in colon cancer are also methylated in a subset of normal colonic cells during the process of aging. In contrast, methylation of the cancer-specific clones was found exclusively in a subset of colorectal cancers, which appear to display a CpG island methylator phenotype (CIMP). CIMP+ tumors also have a high incidence of p16 and THBS1 methylation, and they include the majority of sporadic colorectal cancers with microsatellite instability related to hMLH1 methylation. We thus define a pathway in colorectal cancer that appears to be responsible for the majority of sporadic tumors with mismatch repair deficiency.
National Acad Sciences