CpG Island Methylator Phenotype Associates with Low-Degree Chromosomal Abnormalities in Colorectal Cancer

Abstract

Purpose Aberrant promoter methylation and genomic instability occur frequently during colorectal cancer (CRC) development. CpG island methylator phenotype (CIMP) has been shown to associate with microsatellite instability, BRAF mutation and often found in the right-side colon. Nevertheless, the relative importance of CIMP and chromosomal instability (CIN) for tumorigenesis has yet to be thoroughly investigated in sporadic CRCs. Experimental Design We determined CIMP in 161 primary CRCs and 66 matched normal mucosae using a quantitative bisulfite/PCR/LDR/Universal Array assay. The validity of CIMP was confirmed in a subset of 60 primary tumors using MethyLight assay and five independent markers. In parallel, chromosomal instability was analyzed in the same study cohort using Affymetrix 50K Human Mapping arrays. Results The identified CIMP-positive cancers correlate with microsatellite instability (p=0.075) and the BRAF mutation V600E (p=0.00005). The array-based high-resolution analysis of chromosomal aberrations indicated that the degree of aneuploidy is spread over a wide spectrum among analyzed CRCs. Whether CIN was defined by copy number variations in selected microsatellite loci (criterion 1) or considered as a continuous variable (criterion 2), CIMP-positive samples showed a strong correlation with low-degree chromosomal aberrations (p=0.075 and 0.012, respectively). Similar correlations were observed when CIMP was determined using MethyLight assay (p=0.001 and 0.013, respectively). Conclusion CIMP-positive tumors generally possess lower chromosomal aberrations, which may only be revealed using a genome-wide approach. The significant difference in the degree of chromosomal aberrations between CIMP-positive and the remainder samples suggests that epigenetic (CIMP) and genetic (CIN) abnormalities may arise from independent molecular mechanisms of tumor progression.

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

“…Our findings reveal similar principles of molecular tumorigenesis than recently reported in two comparable studies on colorectal cancer 45,46 ( Figure 2), and indicate that CIMP is related to MSIand MACS-associated intestinal carcinogenesis, whereas it is inversely correlated with CIN. According to our analysis, 50% of small bowel adenocarcinomas are CIN, frequently KRAS mutated, and usually show no or a low level of methylation.…”

“…Figure 2 Comparison of the distribution of CIN, MSI, and MACS in small intestinal adenocarcinoma and colorectal cancer. The results of this study and the average values of two similar studies on colorectal cancer 45,46 are presented. The frequency of CIMP-H in the individual genetic subtypes highlights the predominant occurrence of CIMP-H in MSI and MACS carcinomas.…”

“…These data are in line with a previous observation in colorectal cancer reporting an inverse correlation of aberrant methylation and CIN. 45,46 BRAF mutations have been reported to associate with CIMP-H in colorectal cancer. Our data show that the situation is similar in small bowel cancer.…”

“…The frequency of CIMP-H in the individual genetic subtypes highlights the predominant occurrence of CIMP-H in MSI and MACS carcinomas. *The frequency of CIMP-H in MSI/CIN colorectal carcinomas could only be calculated for one study 45 (0/3 cases).…”

Monoallelic silencing and haploinsufficiency in early murine intestinal neoplasms

“…Loss of function of the APC gene can occur through multiple alternative genetic mechanisms representing many different pathways of pathogenesis (5)(6)(7). The acquisition of some form of genetic instability may be required to accumulate sufficient mutations or imbalances for cancer (8).…”