Abstract
Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'1,2. However, the existence of CIMP has been challenged3,4. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAFmutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1. We propose a robust new marker panel to classify CIMP+ tumors.
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The work described in this manuscript was supported by US National Institutes of Health grant R01 CA075090 awarded to P.W.L.
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Supplementary information
Supplementary Figure 1
Methylation-specific PCR of the New CIMP Panel on CIMP+ and CIMP− colon tumor DNA samples. (PDF 318 kb)
Supplementary Table 1
MethyLight reaction details. (PDF 265 kb)
Supplementary Table 2
New CIMP Classification Panel. (PDF 46 kb)
Supplementary Table 3
Cross-panel classification error rates among various CIMP classification panels, expressed as percentages. (PDF 35 kb)
Supplementary Table 4
Methylation frequency by KRAS and BRAF status. (PDF 44 kb)
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Weisenberger, D., Siegmund, K., Campan, M. et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38, 787–793 (2006). https://doi.org/10.1038/ng1834
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DOI: https://doi.org/10.1038/ng1834
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