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.
Toyota
M
M
The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231, USA.
Ahuja
N
N
Ohe-Toyota
M
M
Herman
J G
JG
Baylin
S B
SB
Issa
J P
JP
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