(original) (raw)

TY - JOUR AU - Weisenberger, Daniel J AU - Siegmund, Kimberly D AU - Campan, Mihaela AU - Young, Joanne AU - Long, Tiffany I AU - Faasse, Mark A AU - Kang, Gyeong Hoon AU - Widschwendter, Martin AU - Weener, Deborah AU - Buchanan, Daniel AU - Koh, Hoey AU - Simms, Lisa AU - Barker, Melissa AU - Leggett, Barbara AU - Levine, Joan AU - Kim, Myungjin AU - French, Amy J AU - Thibodeau, Stephen N AU - Jass, Jeremy AU - Haile, Robert AU - Laird, Peter W PY - 2006 DA - 2006/07/01 TI - CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer JO - Nature Genetics SP - 787 EP - 793 VL - 38 IS - 7 AB - 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. SN - 1546-1718 UR - https://doi.org/10.1038/ng1834 DO - 10.1038/ng1834 ID - Weisenberger2006 ER -