CpG island methylator phenotype in colorectal cancer

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.

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

“…This allowed the colorectal cancers in the cohort to be dichotomized into two groups; positive and negative for regional 3p22 methylation, defined as methylation of 3-5 and 0-2 genes, respectively. This dichotomy is consistent with the criteria used by others for categorizing tumours, as exemplified by CIMP status, 13,14 facilitating analyses between regional 3p22 methylation and other clinicopathological or molecular features that are reported in a categorical manner. However, the present study now shows that regional 3p22 methylation was more frequent in BRAF V600E mutant colorectal cancers regardless of microsatellite stability status, such that methylation of multiple 3p22 genes is not restricted to microsatellite unstable cancers, as we previously reported.…”

“…The CpG island methylator phenotype (CIMP) has been proposed to describe the simultaneous methylation of multiple but discrete CpG islands at distinct loci throughout the genome in the development of a subset of colorectal cancers, now referred to as CIMP þ. [13][14][15] Interestingly, the CIMP þ phenotype also correlates closely with the presence of the BRAF V600E mutation, MLH1 methylation and microsatellite instability, [13][14][15][16] although the basis for the inter-relationship between these genetic and epigenetic phenomena remains unknown. More recently, long-range epigenetic silencing, in which concordant CpG island methylation and chromatin modification across large genomic regions induces silencing of multiple contiguous genes, has also been demonstrated for specific chromosomal regions in a proportion of sporadic colorectal cancers.…”

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

“…DNA methylation plays a major role in colorectal carcinogenesis 30, 31. DNA methylation can be classified into three types (HME, IME and LME) according to the 2‐panel method established by Yagi and Kaneda 18, 19.…”

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

“…Th ese tumors usually have near-diploid karyotypes and harbor a distinct set of driver mutations in genes such as BRAF and TGFBR2 ( 5,6 ). MSI + cancers also oft en exhibit a CpG island methylator phenotype ( 7 ). MSI has been reported by several studies to be a marker of good prognosis in CRC and a meta-analysis of 2,935 stage II or III CRCs found better overall survival for MSI or defective DNA mismatch repair (hazard ratio (HR) = 0.67, 95 % CI 0.58 -0.78) ( 8 ).…”