CpG island methylator phenotype in colorectal cancer.
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.
The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231, USA.
M
M
Toyota
N
N
Ahuja
M
M
Ohe-Toyota
J G
JG
Herman
S B
SB
Baylin
J P
JP
Issa
D048868:Adaptor Proteins, Signal Transducing; D000367:Age Factors; D002352:Carrier Proteins; D003001:Cloning, Molecular; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics; D016147:Genes, Tumor Suppressor; D019942:Genes, p16 / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013447:Sulfites / Q000737:chemistry; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D013447:Sulfites; D000070957:MutL Protein Homolog 1; C042345:hydrogen sulfite