CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations - PubMed (original) (raw)

CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations

Shuji Ogino et al. J Mol Diagn. 2006 Nov.

Abstract

The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation seems to be a distinct epigenotype of colorectal cancer. However, no study has comprehensively examined features of colorectal cancer with less extensive promoter methylation (designated as "CIMP-low"). Using real-time polymerase chain reaction (MethyLight), we quantified DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1] in 840 relatively unbiased, population-based colorectal cancer samples, obtained from two large prospective cohort studies. CIMP-low (defined as 1/5 to 3/5 methylated promoters) colorectal cancers were significantly more common among men (38 versus 30% in women, P = 0.01) and among KRAS-mutated tumors (44 versus 30% in KRAS/BRAF wild-type tumors, P = 0.0003; 19% in BRAF-mutated tumors, P < 0.0001). In addition, KRAS mutations were significantly more common in CIMP-low tumors (47%) than in CIMP-high tumors (with > or =4/5 methylated promoters, 12%, P < 0.0001) and CIMP-0 tumors (with 0/5 methylated promoters, 37%, P = 0.007). The associations of CIMP-low tumors with male sex and KRAS mutations still existed after tumors were stratified by microsatellite instability status. In conclusion, CIMP-low colorectal cancer is associated with male sex and KRAS mutations. The hypothesis that CIMP-low tumors are different from CIMP-high and CIMP-0 tumors needs to be tested further.

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Figures

Figure 1

Figure 1

Frequencies of CIMP-0, CIMP-low, and CIMP-high in KRAS/BRAF wild-type (WT) tumors, _KRAS_-mutated (_BRAF_-wild-type) tumors, and _BRAF_-mutated (_KRAS_-wild-type) tumors. Integer numbers beside bars indicate the actual number of cases with a specific feature (such as CIMP-0, CIMP-low, or CIMP-high). Whereas the frequency of CIMP-0 is higher in KRAS/BRAF wild-type tumors than in _KRAS_-mutated tumors, the frequency of CIMP-low is higher in _KRAS_-mutated tumors than in KRAS/BRAF wild-type tumors.

Figure 2

Figure 2

Frequencies of KRAS mutations among CIMP-0, CIMP-low, and CIMP-high tumors. The KRAS mutation frequency is significantly higher in CIMP-low tumors than in CIMP-high and CIMP-0 tumors.

Figure 3

Figure 3

Frequencies of KRAS mutations in the nine subtypes of colorectal cancers. The KRAS mutation frequency is higher in CIMP-low tumors than in CIMP-high and CIMP-0 tumors among MSI-L/MSS tumors.

Figure 4

Figure 4

Frequencies of BRAF mutations in the nine subtypes of colorectal cancers. The BRAF mutation frequency is very high in CIMP-high tumors and low in CIMP-low and CIMP-0 tumors, regardless of MSI status.

Figure 5

Figure 5

Frequencies of right-sided tumors in the nine subtypes of colorectal cancers. The frequency of right-sided tumors seems to be higher in CIMP-high tumors than CIMP-0 tumors, and CIMP-low tumors show intermediate frequencies within each MSI type.

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