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.
Highlights
Most previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites
Analysis of a large number of CpG sites in the present study revealed that CIMP-H tumors showed a significantly higher KRAS mutation frequency compared to both CIMP-M and CIMP-L tumors (Table 1)
Methylation profiling of 807 cancer-related genes revealed the presence of three CRC subgroups with distinct clinicopathological and molecular features
Summary
Most 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 an effort to establish CIMP+ CRC as a distinct subgroup of CRC, Laird and colleagues analysed the methylation of 195 individual gene promoter regions in 295 CRC using the quantitative MethyLight assay [10]. From their results, they proposed a panel of 5 CpG island methylation markers to standardize the classification of CIMP+ CRC. Nagasaka et al described two distinct patterns of gene methylation in CRC that segregated with BRAF and KRAS mutations [13,16]. Using a panel of 8 methylation markers, Ogino et al identified a CRC subgroup which they termed CIMP-low that was associated with frequent KRAS mutation, MGMT methylation and occurrence in males [17]
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