Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features

Abstract

BackgroundMost previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites. In the present study we performed comprehensive DNA methylation profiling of CRC with the aim of characterizing CIMP subgroups.MethodsDNA methylation at 1,505 CpG sites in 807 cancer-related genes was evaluated using the Illumina GoldenGate® methylation array in 28 normal colonic mucosa and 91 consecutive CRC samples. Methylation data was analyzed using unsupervised hierarchical clustering. CIMP subgroups were compared for various clinicopathological and molecular features including patient age, tumor site, microsatellite instability (MSI), methylation at a consensus panel of CpG islands and mutations in BRAF and KRAS.ResultsA total of 202 CpG sites were differentially methylated between tumor and normal tissue. Unsupervised hierarchical clustering of methylation data from these sites revealed the existence of three CRC subgroups referred to as CIMP-low (CIMP-L, 21% of cases), CIMP-mid (CIMP-M, 14%) and CIMP-high (CIMP-H, 65%). In comparison to CIMP-L tumors, CIMP-H tumors were more often located in the proximal colon and showed more frequent mutation of KRAS and BRAF (P < 0.001).ConclusionsComprehensive DNA methylation profiling identified three CRC subgroups with distinctive clinicopathological and molecular features. This study suggests that both KRAS and BRAF mutations are involved with the CIMP-H pathway of CRC rather than with distinct CIMP subgroups.

Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution

“…Microsatellite instability (MSI), as identified by BAT25 and BAT26 instability (not the full Bethesda panel), was not detected in any of the adenomas, and all had wild-type v-raf murine sarcoma viral oncogene homolog B1 (BRAF), suggesting that the CpG island methylator phenotype (CIMP) was unlikely in these adenomas (19)(20)(21). No significant difference in global genomic DNA methylation level, as measured by pyrosequencing of CpGs within the long, interspersed nuclear element 1 (LINE-1) elements, was seen between the normal and adenomatous epithelium of each patient ( Fig.…”

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

“…[20][21][22][23] It has been argued that CpG island methylation phenotype-positive tumors constitute a distinct subtype of colorectal cancer, and have been variously associated with different features such as BRAF mutation, KRAS mutation, favorable prognosis and adverse outcome. [24][25][26][27][28][29][30]42 These differences are likely related to different criteria used for defining CpG island methylation phenotype-positive status, as well as the number and type of markers used. The role of methylation in signet ring cell carcinoma has not been systematically explored.…”

“…Some, but not all, studies have shown that CpG island methylation phenotype-positive phenotype is associated with aggressive behavior. [26][27][28][29][30] BRAF is a downstream gene in the KRAS pathway. BRAF V600E mutation occurs in 34-80% of cancers with high level of microsatellite instability and 5-15% of microsatellite-stable cancers.…”

DNA Methylation profiling of chronic myelogenous leukemia in relationship to genomic translocation

“…It has been shown that genomic mutations are associated with a high frequency of cancer-specific hypermethylation of particular loci, and these may be associated with distinct DNA methylation subgroups [20][21][22]. Aberrant DNA methylation has been investigated in several types of leukemia in order to gain further insight into cytogenetic subtypes [23][24][25].…”