CpG island methylator phenotype in colorectal cancer

TLDR

Aberrant CpG island methylation in promoters leads to silencing of tumor‑suppressor genes in neoplasia. The study aims to map global CpG island methylation patterns in colorectal cancer. The authors used methylated CpG island amplification to analyze 30 newly cloned differentially methylated DNA sequences. Among the 30 clones, 63 % showed age‑dependent methylation in normal colon, 23 % were cancer‑specific, and 13 % were cell‑line‑specific; most cancer‑methylated CpG islands also appear in aged normal colonic cells, whereas cancer‑specific clones define a CpG island methylator phenotype (CIMP) associated with p16 and THBS1 methylation and the majority of sporadic microsatellite‑instability colorectal cancers linked to hMLH1 methylation, delineating a pathway responsible for most sporadic mismatch‑repair‑deficient tumors.

Abstract

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.